Selective epoxidation process for preparing pharmaceutical compounds

ABSTRACT

Cryptophycin compounds possessing a β-epoxy moiety may be made with high stereoselectivity at various steps in the overall synthetic process. This invention also provides novel intermediates useful in preparing Cryptophycin compounds.

Provisional Application No. 60/034,114 Feb. 26, 1997.

Provisional Application No. 60/034,116 Feb. 26, 1997.

This appln is a 371 of PCT/US98/03667 Feb. 25, 1998.

BACKGROUND OF THE INVENTION

Neoplastic diseases, characterized by the proliferation of cells notsubject to the normal control of cell growth, are a major cause of deathin humans and other mammals. Clinical experience in cancer chemotherapyhas demonstrated that new and more effective drugs are desirable totreat these diseases. Such clinical experience has also demonstratedthat drugs which disrupt the microtubule system of the cytoskeleton canbe effective in inhibiting the proliferation of neoplastic cells.

Cryptophycin compounds can now be prepared using a total syntheticprocess; however, many of the useful cryptophycin compounds contain alabile epoxide group. Barrow, R. A. et al., J. Am. Chem. Soc. 117, 2479(1995). Applicants have discovered that the beta-epoxide can beparticularly desired. However, in the Barrow et al. synthesis of some ofthe cryptophycin compounds of formula (I) below, the epoxidation isperformed in the last step which provides only a 2:1 selectivity for thedesired epoxide. Furthermore, the diasteromers are difficult to separateat this stage. While it would be desirable to epoxidize an earlierintermediate in the process, epoxides are sensitive to a number ofreaction conditions. Moreover, there remains a need for processes withgreater stereoselectivity to avoid difficult diastereomeric separations.

The present invention provides a much desired novel and efficient methodfor preparing cryptophycin compounds having an epoxide functionality.The epoxidation is selective and may be employed at various steps in theoverall synthetic process.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to a process for preparing a compound ofthe formula ##STR1## wherein G is C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl, C₂-C₁₂ alkynyl, or Ar;

Ar is an aromatic or heteroaromatic group or a substituted aromatic orheteroaromatic group;

R³ is C₁ -C₆ alkyl;

R⁴ and R⁵ are each hydrogen; or R⁴ and R⁵ taken together form a secondbond between C-13 and C-14;

R⁷ and R⁸ are each independently hydrogen or C₁ -C₆ alkyl; or

R⁷ and R⁸ taken together form a cyclopropyl or cyclobutyl ring;

R⁹ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,--(CH₂)_(m) --(C₃ -C₅)cycloalkyl or benzyl, wherein m is the integer oneto three;

R¹⁰ is hydrogen or C₁ -C₆ alkyl;

R¹¹ is hydrogen, C₁ -C₆ alkyl, phenyl or benzyl;

R¹⁴ is hydrogen or C₁ -C₆ alkyl;

R⁵⁰ is hydrogen or (═O);

Y' is CH, O, NH, SO, SO₂ or (C₁ -C₃)alkylamino;

R⁶ is C₁ -C₆ alkyl, substituted (C₁ -C₆)alkyl, (C₃ -C₈)cycloalkyl,substituted (C₃ -C₈)cycloalkyl, a heteroaromatic or substitutedheteroaromatic group or a group of formula (IA), (IB) or (IC): ##STR2##R^(6a), R^(6b), and R^(6c) independently are H, halo or OR¹⁸ ; R¹⁵, R¹⁶,and R¹⁷ independently are hydrogen, halo, (C₁ -C₆)alkyl, OR¹⁸, O-aryl,NH₂, NR¹⁸ R¹⁹, NO₂, OPO₄ H₂, (C₁ -C₆ alkoxy)phenyl, S-benzyl, CONH₂, CO₂H, PO₃ H₂, SO₂ R²³, or Z';

R¹⁸ and R¹⁹ independently are hydrogen or C₁ -C₆ alkyl;

R²³ is hydrogen or (C₁ -C₃)alkyl;

Z is --(CH₂)_(n) -- or (C₃ -C₅)cycloalkyl;

n is 0, 1, or 2; and

Z' is an aromatic or substituted aromatic group; or a pharmaceuticallyacceptable salt thereof;

comprising epoxidizing a compound of the formula ##STR3## wherein G, R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴ and R⁵⁰ are as defined above and Yis Y' or S; with an oxidant and a chiral ketone to form a compound offormula (I); and optionally forming a pharmaceutically acceptable saltthereof.

This invention further comprises a process for preparing a compound ofthe formula ##STR4## wherein G is C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl, C₂-C₁₂ alkynyl, or Ar;

Ar is an aromatic or heteroaromatic group or a substituted aromatic orheteroaromatic group;

R³ is C₁ -C₆ alkyl;

R⁴ and R⁵ are each hydrogen; or R⁴ and R⁵ taken together form a secondbond between C-13 and C-14;

R⁸³ is hydrogen, C₁ -C₆ alkyl, trichloroethyl, or --CH₂ SR⁸¹ ;

R³⁰ is hydrogen, an alcohol protecting group, or a group of the formula##STR5## R⁷ and R⁸ are each independently hydrogen or C₁ -C₆ alkyl; or

R⁷ and R⁸ taken together form a cyclopropyl or cyclobutyl ring;

R⁹ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,--(CH₂)_(m) --(C₃ -C₅)cycloalkyl or benzyl, wherein m is the integer oneto three;

R¹⁰ is hydrogen or C₁ -C₆ alkyl;

R¹¹ is hydrogen, C₁ -C₆ alkyl, phenyl or benzyl;

R¹⁴ is hydrogen or C₁ -C₆ alkyl;

R⁵⁰ is hydrogen or (═O);

Y is CH, O, NR¹², S, SO, SO₂, wherein R¹² is H or C₁ -C₃ alkyl;

R⁶ is C₁ -C₆ alkyl, substituted (C₁ -C₆)alkyl, (C₃ -C₈)cycloalkyl,substituted (C₃ -C₈)cycloalkyl, a heteroaromatic or substitutedheteroaromatic group or a group of formula (IA), (IB) or (IC): ##STR6##R^(6a), R^(6b), and R^(6c) independently are H, (C₁ -C₆)alkyl, halo NR¹⁸R¹⁹ or OR¹⁸ ;

R¹⁵, R¹⁶, and R¹⁷ independently are hydrogen, halo, (C₁ -C₆)alkyl, OR¹⁸,O-aryl, NH₂, NR¹⁸ R¹⁹, NO₂, OPO₄ H₂, (C₁ -C₆ alkoxy)phenyl, S-benzyl,CONH₂, CO₂ H, PO₃ H₂, SO₂ R²³, or Z';

R¹⁸ and R¹⁹ independently are hydrogen or C₁ -C₆ alkyl;

R²³ is hydrogen or (C₁ -C₃)alkyl;

Z is --(CH₂)_(n) -- or (C₃ -C₅)cycloalkyl;

n is 0, 1, or 2; and

Z' is an aromatic or substituted aromatic group;

R⁸¹ is C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, phenyl or benzyl; and

R⁸² is a base labile protecting group; or a pharmaceutically acceptablesalt thereof; with the proviso that when R⁸³ is --CH₂ SR⁸¹, R³⁰ is nothydrogen or an alcohol protecting group; with the further proviso thatwhen R⁸³ is trichloroethyl, R³⁰ is not an alcohol protecting group;

comprising epoxidizing a compound of the formula ##STR7## wherein G, R³,R⁴, R⁵, R⁶, R¹⁴, R³⁰ and R⁸³ are as defined above; with an oxidant and achiral ketone to form a compound of formula (II); and optionally forminga pharmaceutically acceptable salt thereof. The compounds of formula(II) are useful as intermediates in preparing compounds of formula (I).

This invention further comprises the novel compounds of formulae (IId),(18) and (19), disclosed herein, useful in the preparation of compoundsof formula (I).

DETAILED DESCRIPTION OF THE INVENTION

As used in the application:

(a) the designation "" refers to a bond that protrudes forward out ofthe plane of the page;

(b) the designation "" refers to a bond that protrudes backward out ofthe plane of the page; and

(c) the designation "" refers to a bond for which the stereochemistry isnot designated.

As used herein, the term "pharmaceutically acceptable salt" refers toeither acid addition salts or base addition salts.

The expression "pharmaceutically acceptable acid addition salt" isintended to apply to any non-toxic organic or inorganic acid additionsalt of the compounds of formula I or any of its intermediates.Illustrative inorganic acids which form suitable salts includehydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metalsalts such as sodium monohydrogen orthophophate, and potassium hydrogensulfate. Illustrative organic acids which form suitable salts includethe mono-, di- and tricaboxylic acids. Illustrative of such acids arefor example, acetic, glycolic, lactic, pyruvic, malonic, succinic,glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic,hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,salicylic, 2-phenoxy-benzoic, and sulfonic acids such asp-toluenesulfonic acid, methane sulfonic acid and 2-hydroxyethanesulfonic acid. Such salts can exist in either hydrated or substantiallyanhydrous form.

The expression "pharmaceutically acceptable basic addition salts" isintended to apply to any non-toxic organic or inorganic basic additionsalts of the compounds of formula I or any of its intermediates.Illustrative bases which form suitable salts include alkali metal oralkaline-earth metal hydroxides such as sodium, potassium, calcium,magnesium or barium hydroxides; ammonia and aliphatic, cyclic oraromatic organic amines such as methylamine, dimethylamine,trimethylamine, diethylamine, triethylamine, isopropyldiethylamine,pyridine and picoline.

As used herein, the term "C₁ -C₁₂ alkyl" refers to a saturated straightor branched chain hydrocarbon group of from one to twelve carbon atoms.Included within the scope of this term are methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl,2-methylbutyl, 3-methylbutyl, hexyl, heptyl, octyl, nonyl, decyl and thelike. Included within the term is the term "C₁ -C₆ alkyl" which refersto a saturated, unsaturated, straight or branched chain hydrocarbonradical of from one to six carbon atoms. Included within the scope ofthis term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, neopentyl, 2-methylbutyl, 3-methylbutyl,hexyl and the like. Included within the terms "C₁ -C₁₂ alkyl" and "C₁-C₆ alkyl" is the terms "C₁ -C₃ alkyl" which refers to a saturated,unsaturated, straight or branched chain hydrocarbon radical of from oneto three carbon atoms. Included within the scope of this term aremethyl, ethyl, isopropyl, and the like.

"Substituted (C₁ -C₆)alkyl" refers to a C₁ -C₆ alkyl group that mayinclude up to three (3) substituents containing one or more heteroatoms.Examples of such substituents are OH, NH₂, CONH₂, CO₂ H, PO₃ H₂ and SO₂R²¹ wherein R²¹ is hydrogen, C₁ -C₃ alkyl or aryl.

The term "(C₃ -C₈)cycloalkyl" refers to a saturated C₃ -C₈ cycloalkylgroup. Included within this group are cyclopropyl, cyclobutyl,cyclohexyl, cyclooctyl, and the like. A "substituted (C₃ -C₈)cycloalkylgroup" refers to a (C₃ -C₈)cycloalkyl group having up to three C₁ -C₃alkyl, halo, or OR²¹ substituents. The substituents may be attached atany available carbon atom. Cyclohexyl is an especially preferredcycloalkyl group. The term "--(CH₂)_(m) --(C₃ -C₅) cycloalkyl" where mis an integer one, two or three refers to a cyclopropyl, cyclobutyl orcyclopentyl ring attached to a methylidene, ethylidene or propylidenesubstituent.

The term "C₂ -C₁₂ alkenyl" refers to an unsaturated straight or branchedchain hydrocarbon radical of from two to twelve carbon atoms and havingfrom one to three double bonds. Included within the scope of this termare ethenyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl,2-methylbutenyl, 3-methylbutenyl, hexenyl, octenyl, nonenyl, decenyl andthe like. It is especially preferred that alkenyl have only one doublebond.

The term "C₂ -C₁₂ alkynyl" refers to an unsaturated straight or branchedchain hydrocarbon radical of from two to twelve carbon atoms and havingfrom one to three triple bonds. Included within the scope of this termare ethynyl, propynyl, isopropynyl, 2-methypropynyl, hexynyl, decynyl,and the like. It is particularly preferred that alkynyl has only onetriple bond.

The term "C₁ -C₆ alkoxy" refers to a straight or branched alkoxy groupcontaining from one to six carbon atoms, such as methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, pentoxy, 2-methylpentoxy,and the like. The term "(C₁ -C₆ alkoxy)phenyl" refers to a phenyl groupsubstituted with a C₁ -C₆ alkoxy group at any available carbon on thephenyl ring.

The term "halo" refers to chloro, bromo, fluoro, or iodo.

The terms "aromatic group" and "heteroaromatic group" refer to commonaromatic rings having 4n+2 pi electrons in a monocyclic or bicyclicconjugated system. The term "aryl" refers to an aromatic group, and theterm "aralkyl" refers to an aryl(C₁ -C₆ -alkyl) group. Examples ofaromatic groups are phenyl, benzyl and naphthyl. Heteroaromatic groupswill contain one or more oxygen, nitrogen and/or sulfur atoms in thering. Examples of heteroaromatic groups include furyl, pyrrolyl,thienyl, pyridyl and the like. When the aromatic or heteroaromaticgroups are substituted, they may have from one to three independentlyselected C₁ -C₆ alkyl, C₁ -C₆ -alkoxy or halo, substituents. Thearomatic groups may be further substituted with trifluoromethyl, COOR⁵⁷(wherein R⁵⁷ is hydrogen or C₁ -C₆ alkyl), PO₃ H, SO₃ H, SO₂ R⁵⁷, N(R⁵⁹)(R⁶⁰) (wherein R⁵⁹ is hydrogen or C₁ -C₆ alkyl and R⁶⁰ is hydrogen, C₁-C₆ alkyl, BOC or FMOC), --CN, --NO₂, --OR⁵⁷, --CH₂ OC(O) (CH₂)_(m') NH₂(wherein m' is an integer 1 to 6) or --CH₂ --O--Si(R⁵⁷) (R⁵⁸) (R⁵⁹)(wherein R⁵⁸ is hydrogen or C₁ -C₆ alkyl). Especially preferredsubstituents for the aromatic groups include methyl, halo, N(R⁵⁹) (R⁶⁰),and --OR⁵⁷. The substituents may be attached at any available carbonatom.

Especially preferred heterocyclic or substituted heterocyclic groupsinclude ##STR8## wherein R²⁰ is hydrogen or C₁ -C₆ alkyl.

The term "aryl" refers to an aromatic group of from 6 to 12 carbonatoms, such as phenyl or naphthyl groups wherein said groups areoptionally substituted with one, two or three substituents selected fromthe group consisting of C₁ -C₄ alkyl, halo-substituted C₁ -C₄ alkyl,halogen or C₁ -C₄ alkoxy. The terms "lower alkoyl group" or "C₁ -C₅alkoxy" refers to an alkyloxy radical made up of an oxygen radicalbearing a saturated straight or branched chain hydrocarbyl radical ofone to five carbon atoms and specifically includes methoxy, ethoxy,propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tertiarybutyloxy, pentyloxy and the like. Specifically included with the scopeof the term "aryl" are phenyl, p-toluoyl, p-methoxyphenyl,p-chlorophenyl, naphthyl and the like.

As used herein, the term "heteroaryl" refers to a substituted orunsubstituted heteroaromatic radical which contains one or morenon-carbon substituents within the ring, said substituents selected fromoxygen, nitrogen or sulfur. The total number of carbon atoms andnon-carbon atoms in the ring range from four to twelve atoms.Specifically included with the scope of the term "heteroaryl" aremonocyclic conjugated systems such as furyl, pyrrolyl, thienyl, pyridyl,and the like and bicyclic conjugated systems such as indole.

As used herein "epoxide ring" means a three-membered ring whose backboneconsists of two carbons and an oxygen atom. As used herein, "aziridinering" means a three-membered ring whose backbone consists of two carbonatoms and a nitrogen atom. As used herein "sulfide ring" means athree-membered ring whose backbone consists of two carbon atoms and asulfur atom. As used herein "episulfide ring" means a three-memberedring whose backbone consists of two carbon atoms and a sulfur atom. Asused herein "sulfate group" means a five membered ring consisting of acarbon--carbon--oxygen--sulfur--oxygen backbone with two additionaloxygen atoms connected to the sulfur atom. As used herein "cyclopropylring" means a three member ring whose backbone consists of three carbonatoms. As used herein, "monoalkylphosphate ring" means a five memberedring consisting of a carbon--carbon--oxygen--phosphorous--oxygenbackbone with two additional oxygen atoms, one of which bears a loweralkyl group, connected to the phosphorous atom.

As used herein, the term "(═O)" in combination with the carbon on thering to which it is attached refers to a carbonyl group of the formula##STR9##

The term "O-aryl" refers to an aryloxy or an aryl group bonded to an oxymoiety.

As used herein, the term "Ph" refers to a phenyl moiety.

As used herein, the term "TBS" refers to tert-butyldimethylsilyl asrepresented by the formula ##STR10##

As used herein, the term "NHS" refers to a N-hydroxysuccinimide moietyof the formula ##STR11##

As used herein the term "base labile amino protecting group" refers tocommon amino protecting groups which are known to be base labile. Theartisan can consult common works such as Greene, T. W. "ProtectingGroups in Organic Synthesis", Wiley (New York, 1981). See particularlyChapter 7 of Greene. An especially preferred base labile aminoprotecting group is fluorenylmethoxycarbonyl (Fmoc).

The term "suitable activatable carboxy protecting group" refers tocarboxy protecting groups containing activatable ester substituents andare known by one of ordinary skill in the art and disclosed by Greene,T. W., supra. Suitable carboxy protecting groups are those which areactivatable ester substituents including N-hydroxy-succinimide,N-hydroxysulfosuccinimide and salts thereof, 2-nitrophenyl,4-nitrophenyl, 2,4-dichlorophenyl, and the like. An especially preferredactivatable carboxy protecting group is N-hydroxy-succinimide (NHS).

As used herein, the term "oxidant" has the meaning associated with theterm by the artisan. For example, an oxidant is an agent capable ofconverting an alkene moiety of a chemical intermediate of this inventionto an epoxide moiety. Suitable oxidants include potassiumperoxomonosulfate (Oxone), m-CPBA, methyltrioxorhenium (VII),trifluoroper-acetic acid, and magnesium monoperoxyphthalate. A preferredoxidant is potassium peroxomonosulfate (Oxone).

As used herein, the term "chiral ketone" refers to a ketone containingthe following general features:

1) the stereogenic centers are close to the reacting center; and

2) the ketone has a fused ring and a a quaternary center α to a carbonylgroup; and

3) one face of the ketone is sterically blocked. One especiallypreferred chiral ketone is of the structure: ##STR12##

As used herein the term "alcohol protecting group" can be selected usingcommon works. The term refers to alcohol protecting groups that can beselected from works such as Greene, T. W. "Protecting Groups in OrganicSynthesis", Wiley (New York, 1981). See especially Chapter 2 of Greene.Preferred alcohol protecting groups are selected from silyl and acylgroups. An especially preferred group is tert-butyldimethylsilyl (TBS).

A general synthetic procedure for preparing a compound of formula (I) isset forth in Scheme A. In Scheme A, all substituents unless otherwiseindicated, are as previously defined. Reagents, techniques, andprocedures used in Scheme A are well known and appreciated by one ofordinary skill in the art. ##STR13##

In Scheme A, an alkene of formula (4) is epoxidized with a chiral ketoneand an oxidant to form a β-epoxide of formula (I).

For example, a compound of formula (4) may be stereoselectivelyepoxidized to form a β-epoxide of formula (I) using a chiral ketone withan oxidant in the presence of a suitable base such as NaHCO₃ usingprocedures analogous to those disclosed by Tu, Y. et al, J. Am. Chem.Soc. 118, 9806 (1996); Wang, Z-X et al. J. Org. Chem. 62, 2328 (1997);Wang, Z-X et al., J. Am. Chem. Soc. 119, 11224 (1997). Preferredcompounds of formula (4) for this reaction include those compounds whereG is phenyl, R³ is methyl, R⁴ and R⁵ form a second bond, R¹⁴ ishydrogen, R¹¹ is hydrogen, R⁵⁰ is (═O), and Y is O. The preferredoxidant is Oxone and the preferred chiral ketone is the compound offormula (7).

This preferred chiral ketone can be prepared from D-fructose byketalization and oxidation under routine conditions. For example, theketalization can be completed using acetone, HClO₄, and the process isconducted at about 0° C. For example, the oxidation can be completedusing pyridinium chlorochromate at room temperature. These reactions areknown in the art; see, for example: Tu, Y. et al, supra. and Wang, Z-Xet al. supra. The asymmetric epoxidation can be carried out at a pHwithin the range of from about 7.0 to about 11.5.

Although it requires about 3-4 equivalents of chiral ketone to obtainconversions of greater than 95% with many cryptophycin intermediates ata pH of about 8.0, it is possible to use less chiral ketone (about 1-2equivalents) at a pH of about 9.0 or above. Suitable solvents useful forthe epoxidation step include H₂ O, DMF, glyme, dioxane, CH₃ CN,alcohols, THF, EtOAc, halohydrocarbons, chlorobenzene, and toluene, witha CH₃ CN/H₂ O solvent combination being preferred. Reaction temperaturesmay range from about -20° C. to about 25° C. with about -10° C. to about10° C. being preferred. The β-epoxide of formula (I), can be isolatedand purified by techniques well known in the art such as extraction,evaporation, chromatography and recrystallization. A preferredstereoselective epoxidation utilizes the chiral ketone of structure (7)to provide a mixture of epoxides (α and β) in the crude product (I) inthe ratio of about α:β 1:5. This procedure can also be utilizedanalogously to obtain the α-epoxide derivative of formula (I).

The alkenes of formula (4) are known and may be prepared according totechniques and procedures known in the art. Barrow, R. A. et al. J. Am.Chem. Soc. 117, 2479 (1995); PCT Intnl. Publ. No. WO 97/07798, publishedMar. 6, 1997, PCT Intnl. Publ. No. WO 96/40184, published Dec. 19, 1996.

A general synthetic procedure for preparing a compound of formula (II),useful as an intermediate for making the β-epoxides of formula (I), isset forth in Scheme B. In Scheme B, R^(83') is hydrogen or C₁ -C₆ alkyl;R⁸³ is a base labile protecting group; R^(30') is an alcohol protectinggroup; and q is an integer 1 or 2. All other substituents unlessotherwise indicated, are as previously defined. Reagents, techniques,and procedures used in Scheme B are well known and appreciated by one ofordinary skill in the art. ##STR14##

In Scheme B, step 1, an alkene of formula (5a) is epoxidized with achiral ketone and an oxidant according to the procedure set forth inScheme A to form a fragment A-B β-epoxide of formula (IIa).

In Scheme B, step 2, a fragment A-B β-epoxide of formula (IIa) isdeprotected with a suitable alkoxy deprotecting agent to form a compoundof formula (IIb).

A suitable alkoxy deprotecting agent is one that removes the hydroxyprotecting group signified by the R^(30') substituent while inert to theepoxide moiety of the fragment A-B compound of formula (IIa). Preferreddeprotecting agents include basic fluoride sources such astetrabutylammonium fluoride, pyridinium fluoride, triethylammoniumfluoride, cesium fluoride, and the like, with tetrabutylammoniumfluoride being preferred. The deprotection reaction takes place in thepresence of a suitable organic solvent such as tetrahydrofuran,optionally in the presence of a suitable base, such as sodiumbicarbonate (NaHCO₃). The reaction takes place in the range of fromabout 0° C. to about 80° C. with from about 20° C. to about 70° C. beingpreferred. The reaction is run for a period of time ranging from about 3to 24 hours. Crude product (IIb) may be used without furtherpurification. Alternatively, the compound of formula (IIb) may beisolated and purified according to procedures well known well known inthe art such as extraction, evaporation, chromatography andrecrystallization.

In Scheme B, step 3, the compound of formula (IIb) is contacted with athioester forming agent to provide the thioester of formula (IIc).

The term "thioester forming agent" encompasses any suitable means orconditions for forming the thioester moiety of formula (IIc). Includedwithin this definition are the conditions set forth and/or analogouslydescribed in Ono, N. et al., Bull. Chem. Soc. Jpn. 51 (8), 2401 (1978);Ho, Tse-Lok, Synth. Comm. 9(4), 267-270 (1979); Narasaka, K. et al., J.Am. Chem. Soc. 106 (10), 2954-2960 (1984); L. G. Wade, Jr. et al.,Tetrahedron Lett. 731-732 (1978); Mora, N. et al., Tetrahedron Lett. 34(15), 2461-2464 (1993); and Dossena, A. et al. J. Chem. Soc. PerkinTrans. I, 2737 (1981).

For example, the compound of formula (IIb) may be treated with asterically hindered alkyl halide, such as tert-butylbromide, and asolvent of the formula (R⁸¹)(Me)SO, wherein R⁸¹ is as defined above, inthe presence of a suitable base, such as sodium bicarbonate (NaHCO₃). Apreferred solvent for reaction is dimethylsulfoxide (DMSO). Both thesterically hindered alkyl halide and the suitable base are added in amolar excess of about 7.0 to 12.0 in comparison to the compound offormula (IIb). The reaction takes place in the range of from about 0° C.to about 60° C. with from about 10° C. to about 30° C. being preferred.The reaction is run for a period of time ranging from about 1 to 24hours. Crude product (IIc) may be used without further purification.Alternatively, the thioester of formula (IIc) may be isolated andpurified according to procedures well known well known in the art suchas extraction, evaporation, chromatography and recrystallization.

In those instances when the substituent R^(83') is a moiety other thanhydrogen, the compound of formula (IIb) must first becarboxy-deprotected. Carboxy-deprotections under basic conditions areknown by those of ordinary skill in the art. For example, the compoundof formula (IIb) may be treated with a suitable base, such as lithiumhydroxide (LiOH) for a period of time sufficient to remove the carboxyprotecting group, for example from about 1 to 24 hours.

In Scheme B, step 4, a β-epoxy thioester of formula (IIc) is coupledwith a carboxylic acid of the formula ##STR15## wherein R⁷, R⁸, R⁹, R¹⁰,R¹¹, R⁵⁰ and R⁸² are as defined above to provide the compound of formula(8).

For example, the carboxylic acid of formula (10a) is dissolved in asuitable organic solvent, such as DMF, glyme, dioxane, THF, CH₃ CN,EtOAc, and halohydrocarbons, with dichloromethane being preferred. Thissolution is then treated with a coupling reagent. Possible couplingreagents include DCC, EDCI, and similar reagents, such as DMAP whichactivate carboxylic acids towards esterification with alcohols. Thissolution may then be optionally treated with a suitable base such assolid sodium bicarbonate and then contacted with a β-epoxy thioester offormula (IIc). The concentration of (10a) after these additions shouldrange from about 0.1 M to about 2.0 M. The reaction takes place in therange of from about -30° C. to about 60° C. with from about 10° C. toabout 30° C. being preferred. The reaction is run for a period of timeranging from about 0.5 to 12 hours. Crude product (8) may be usedwithout further purification. Alternatively, the compound of formula (8)may be isolated and purified according to procedures well known wellknown in the art such as extraction, evaporation, chromatography andrecrystallization.

In Scheme B, step 5, a β-epoxy thioester of formula (8) is oxidized witha suitable oxidizing agent to provide the sulfone or sulfoxide offormula (9).

A suitable oxidizing agent is an agent capable of converting the sulfideof formula (8) into the sulfone or sulfoxide of formula (9), while inertto the epoxide moiety of the molecule. Suitable oxidizing agents includepotassium peroxomonosulfate (Oxone), m-CPBA, methyltrioxorhenium(VII),and magnesium monoperoxyphthalate, with Oxone being preferred.

For example, the sulfide of formula (8) is treated with a suitable base,such as sodium bicarbonate followed by a suitable oxidizing agent, suchas Oxone. The reaction is carried out in a suitable solvent, such asacetone, DMF, glyme, dioxane, CH₃ CN, alcohols, THF, EtOAc,halohydrocarbons, chlorobenzene, and toluene, with acetone beingpreferred. Generally, the reaction is carried out at temperatures offrom about -30° C. to about 50° C. with from about -10° C. to about 10°C. being preferred. Generally, the reaction requires from about 15minutes to about 5 hours. Crude sulfone or sulfoxide (9) may be usedwithout further purification. Alternatively, the sulfone or sulfoxide offormula (9) may be isolated and purified according to procedures wellknown well known in the art such as extraction, evaporation,chromatography and recrystallization.

In Scheme B, step 6, the sulfone or sulfoxide of formula (9) isdeprotected with a suitable deprotecting agent to provide the amine offormula (10).

A suitable deprotecting agent is an agent capable of removing the baselabile substituent R⁸² on the compound of formula (9) while inert to theepoxide moiety of the molecule. Suitable deprotecting agents includebases such as secondary and tertiary amines and inorganic bases, forexample, piperidine; morpholine, dicyclohexylamine,p-dimethylaminopyridine, diisopropylethylamine, and the like, withpiperidine being preferred. The reaction is carried out in a suitablesolvent such as DMF, glyme, dioxane, CH₃ CN, alcohols, THF, EtOAc,halohydrocarbons, chlorobenzene, or toluene. Generally, the reaction iscarried out at a temperature ranging from about 0° C. to about 120° C.Generally, the reaction requires from about 1 to 72 hours. The compoundof formula (I) may be isolated and purified by techniques well known inthe art, such as extraction, evaporation, chromatography andrecrystallization. Alternatively, the compound of formula (10) isisolated and may be further cyclized with a cyclizing agent to provide acompound of formula (I).

Typically, once the compound of formula (9) is deprotected, it undergoesspontaneous cyclization. However, some particular compounds of formula(9) may require an additional cyclization step. For example, the sulfideof formula (8), although much less active than its oxidized counterpart,upon removal of the base-labile protecting group may be cyclized with asuitable cyclizing agent, such as 2-hydroxypyridine to form a compoundof formula (I). For example, the sulfide of formula (8), oralternatively a selected compound of formula (10), is heated in asuitable solvent, such as DMF at about 60° C. for several days in thepresence of piperidine and 2-hydroxypyridine. The compound of formula(I) is isolated and purified by techniques well known in the art, suchas extraction, evaporation, chromatography and recrystallization.

Alternatively, a compound of formula (9) may be formed according toSCHEME B1. In SCHEME B1, all substituents are as previously definedexcept where otherwise indicated. ##STR16## In SCHEME B1, alkene offormula (11) is epoxidized with a chiral ketone and an oxidant accordingto the procedure set forth in Scheme A to form a compound of formula(9). The alkene of formula (11) may be prepared by one of ordinary skillin the art according to analogously known techninques and procedures.During the epoxidation reaction, the sulfide moiety of compound (11) isoxidized to form the sulfoxide or sulfone moiety of compound (9).

Optionally, on those compounds of formula (I) containing basic or acidicfunctional groups, pharmaceutically acceptable salts of the compounds offormula (I) may be formed using standard techniques. For example, thefree base may be dissolved in aqueous or aqueous-alcohol solution orother suitable solvent containing the appropriate acid and the saltisolated by evaporating the solution. Alternatively, the free base maybe reacted in an organic solvent containing the appropriate acid and thesalt isolated by evaporating the solution. Further, the free base may bereacted in an organic solvent in which case the salt separates directlyor can be obtained by concentration of the solution or in a solvent suchas water which is then removed in vacuo or by freeze-drying, or byexchanging the cations of an existing salt for another cation on asuitable ion exchange resin.

A synthetic scheme for making the carboxylic acids of formula (10a) isset forth in Scheme C. The reagents and starting material are readilyavailable to one of ordinary skill in the art. In Scheme C, allsubstituents, unless otherwise indicated, are as previously defined.##STR17##

In Scheme C, step 1, the Boc-protected amine of formula (14) isdeprotected to provide the deprotected amine of formula (15).

For example, the deprotection reaction involves the removal of an aminoprotecting group by techniques and procedures well known and appreciatedby one of ordinary skill in the art. The selection, use, and removal ofprotecting groups are set forth by Greene, T. W. "Protecting Groups inOrganic Synthesis", Wiley (New York, 1981). For example, theBoc-protected amine of formula (14) is dissolved in a suitable acid,such as trifluoroacetic acid or hyrdrochloric acid. Generally, thereaction is carried out at a temperature ranging from about 0° C. toabout 60° C. Generally, the reaction requires from about 1 to 24 hours.The deprotected amine of formula (15) may be isolated and purified bytechniques well known in the art, such as extraction, evaporation,chromatography and recrystallization.

The Boc-protected amine of formula (14) is described in Barrow, R. A. etal. J. Am. Chem. Soc. 117, 2479 (1995); PCT Intnl. Publ. No. WO96/40184, published Dec. 19, 1996; and PCT Intnl. Publ. No. WO 97/07798,published Mar. 6, 1997.

In Scheme C, step 2, the deprotected amine of formula (15) isamino-protected with a base-labile amino protecting group to provide thecarboxylic acid of formula (10a).

For example, the protection of an amino group with a base-labile aminoprotecting group involves the addition of a base-labile amino protectinggroup by techniques and procedures well known and appreciated by one ofordinary skill in the art. The selection, use, and removal ofbase-labile amino protecting groups are set forth by Greene, T. W."Protecting Groups in Organic Synthesis", Wiley (New York, 1981). Apreferred base-labile amino protecting group is Fmoc. For example, to asolution of the deprotected amine of formula (15) in a suitable solvent,such as dioxane, is added a suitable base, such as sodium bicarbonate,followed by a compound of the formula R⁸² -Cl or R⁸² -NHS, such asFmoc-Cl or Fmoc-NHS succinimide. The mixture may be optionally dilutedwith a small amount of water and stirred for a period of time rangingfrom 12 to 48 hours at a temperature ranging from about 0° C. to about60° C. The mixture may be quenched with a suitable acid, such ashydrochloric acid. The carboxylic acid of formula (10a) may be isolatedand purified by techniques well known in the art, such as extraction,evaporation, chromatography and recrystallization.

A synthetic scheme for making a compound of formula (II) wherein R⁸³ istrichloroethyl is set forth in Scheme D. The reagents and startingmaterial are readily available to one of ordinary skill in the art. InScheme D, all other substituents, unless otherwise indicated, are aspreviously defined. ##STR18##

In Scheme D, step 1, the alkene of formula (16) is epoxidized with achiral ketone and an oxidant according to the procedure set forth inScheme A to form a β-epoxy compound of formula (IId).

In Scheme D, step 2, a β-epoxy compound of formula (IId) is coupled witha carboxylic acid of formula (10a) according to the procedures describedin Scheme B, step 4, to form a compound of formula (18).

In Scheme D, step 2A, an alkene of formula (17) is epoxidized with achiral ketone and an oxidant according to the procedure set forth inScheme A to form a compound of formula (18).

In Scheme D, step 3, the compound of formula (18) is base-deprotectedwith a suitable base-deprotecting agent to provide the compound offormula (19).

A suitable base-deprotecting agent is an agent that is capable ofremoving the base labile substituent R⁸² on the compound of formula (18)while inert to the epoxide moiety of the molecule. Suitablebase-deprotecting agents include bases such as secondary and tertiaryamines and inorganic bases, for example, piperidine, morpholine,dicyclohexylamine, p-dimethylaminopyridine, diisopropylethylamine, andthe like, with piperidine being preferred. These agents are set forth inGreene, T. W. "Protecting Groups in Organic Synthesis", Wiley (New York,1981). The reaction is carried out in a suitable solvent such as DMF,glyme, dioxane, CH₃ CN, alcohols, THF, EtOAc, halohydrocarbons,chlorobenzene, or toluene. Generally, the reaction is carried out at atemperature ranging from about 0° C. to about 120° C. Generally, thereaction requires from about 1 to 72 hours. The compound of formula (19)may be isolated and purified by techniques well known in the art, suchas extraction, evaporation, chromatography and recrystallization.

Typically, once the compound of formula (18) is deprotected, itundergoes spontaneous cyclization to provide a compound of formula (I).However, some particular compounds of formula (18) may yield a compoundof formula (19) after deprotection and require an additionalring-closing step as set forth in Scheme D, step 4.

In Scheme D, step 4, the compound of formula (19) is cyclized using aring-closing agent to provide a compound of formula (I).

The ring-closing reaction may be carried out by intramolecularaminolysis. For example, the compound of formula (19) is treated with asuitable cyclizing agent such as 2-hydroxypyridine analogous to thedeprotection and cyclization conditions described in Scheme B, steps 6and 7 to provide a compound of formula (I).

The pharmaceutically acceptable salts of a compound of formula (I),prepared as described in Scheme D, may optionally be formed according tothe procedures described in Scheme B.

Some preferred characteristics of this invention are set forth in thefollowing tabular form wherein the features may be independentlyselected to provide preferred embodiments of this invention. Theinvention is in no way limited to the features described below:

A) R⁸ is ethyl, propyl, isopropyl, butyl, isobutyl or isopentyl;

B) R⁷ is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, orisopentyl;

C) R⁷ is H, R⁸ is methyl, R³ is methyl, and X and Y are not both O;

D) R³ is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl;

E) R⁹ is methyl, ethyl, propyl, butyl, isobutyl, pentyl, or isopentyl;

F) R¹⁰ is methyl, ethyl, propyl, butyl, isobutyl, pentyl, or isopentyl;

G) Ar is phenyl optionally substituted with a substituent selected fromthe group consisting of hydrogen, halogen, and simple alkyl;

H) a compound wherein Y is selected from the group consisting of O, NH,S, SO and SO₂ ;

I) a compound wherein Y is C, R⁷, R⁸, R⁹, and R¹⁰ are each hydrogen; andR¹ and R² form an epoxide;

J) R⁷, R⁸ are each hydrogen;

K) R⁷ and R⁸ are each selected from hydrogen or OH;

L) Y is NH;

M) R is selected from the group consisting of methyl, ethyl, n-propyl,and phenyl;

N) X is O and Y is NH;

O) R⁴ and R⁵ form a double bond;

P) R⁶ is substituted benzyl wherein one substituent is a halogen and oneis an OR¹² group wherein R¹² is lower alkyl;

Q) the oxidant is Oxone;

R) the process is utilized to prepare a cryptophycin compound;

S) the epoxidation is selective;

T) the ketone is of the formula: ##STR19## U) R^(p) is NHS; and V) R⁷and R⁸ are each methyl.

To provide further guidance for the artisan, the following schemes areprovided: ##STR20##

As used in Scheme I' and throughout the specification, R^(1') ishalogen, SH, amino, monoalkylamino, dialkylamino, trialkylammonium,alkylthio, dialkylsulfonium, sulfate, phosphate or a protected OH orprotected SH group; R² is OH or SH; R²⁶ is an alcohol protecting groupintroduced during a portion of the synthetic process to protect analcohol group which might otherwise react in the course of chemicalmanipulations, and is then removed at a later stage of the synthesis.Numerous reactions for the formation and removal of such a protectinggroups are described in a number of standard works, including, forexample, "Protective Groups in Organic Chemistry", Plenum Press, (Londonand New York, 1973); Greene, T. W. "Protecting Groups in OrganicSynthesis", Wiley (New York, 1981). The skilled artisan can select anappropriate alcohol protecting group particularly with guidance providedfrom such works. One particularly useful alcohol protecting group istert-butyldimethylsilyl (TBS). ##STR21##

As used in Scheme I' and throughout the specification, R^(1') ishalogen, SH, amino, monoalkylamino, dialkylamino, trialkylammonium,alkylthio, dialkylsulfonium, sulfate, or phosphate; R² is OH or SH; R²⁶is an alcohol protecting group introduced during a portion of thesynthetic process to protect an alcohol group which might otherwisereact in the course of chemical manipulations, and is then removed at alater stage of the synthesis. Numerous reactions for the formation andremoval of such a protecting group are described in a number of standardworks, including, for example, "Protective Groups in Organic Chemistry",Plenum Press, (London and New York, 1973); Greene, T. W. "ProtectingGroups in Organic Synthesis", Wiley (New York, 1981). The skilledartisan can select an appropriate alcohol protecting group particularlywith guidance provided from such works. One particularly useful alcoholprotecting group is tert-butyldimethylsilyl (TBS). The products of suchschemes can be derivatized using standard methods to provide othercryptophycin compounds. ##STR22## R⁶ has the meaning defined supra.##STR23##

The product of the schemes provided herein can be further derivatizedusing standard methods to provide further cryptophycin compounds.

The artisan can utilize appropriate starting materials and reagents toprepare desired compounds using the guidance of the previous schemes andfollowing examples.

The ester starting material can be prepared, for example, as follows:##STR24## R⁶ has the meaning defined supra.

The scheme for preparing the ester is further explained by thePreparation Section herein which provides one specific application ofthe scheme for the convenience of the skilled artisan.

The Scheme for preparing the ester is applicable to the Ar substituentsclaimed herein. The scheme illustration is not intended to limited thesynthesis scheme only to the phenyl ring illustrated. Rather, theartisan can broadly apply this process to provide desired startingmaterials for the compounds claimed herein.

The scheme for preparing the ester is further explained by thePreparation Section herein which provides one specific application ofthe scheme for the convenience of the skilled artisan.

Scheme E for preparing the ester is applicable to the Ar substituentsclaimed herein. The scheme illustration is not intended to limited thesynthesis scheme only to the phenyl ring illustrated. Rather, theartisan can broadly apply this process to provide desired startingmaterials for use in the processes claimed herein.

The necessary reaction time is related to the starting materials andoperating temperature. The optimum reaction time for a given process is,as always, a compromise which is determined by considering the competinggoals of throughput, which is favored by short reaction times, andmaximum yield, which is favored by long reaction times.

To further illustrate the invention the following examples are provided.The scope of the invention is in no way to be construed as limited to orby the following examples.

Preparation 1

Step 1. Methyl 5-Phenylpent-2(E)-enoate ##STR25## A solution oftrimethyl phosphonoacetate (376 g, 417 mL, 2.07 mol) in THF (750 mL) wasstirred at 0° C. in a 3 L 3-neck round bottom flask equipped with amechanical stirrer and N₂ inlet. To the chilled solution, neattetramethyl guanidine (239 g, 260 mL, 2.07 mol) was added dropwise viaan addition funnel. The chilled clear pale yellow solution was stirredfor 25 minutes at 0° C. A solution of hydrocinnamaldehyde (90%, 253 g,248 mL, 1.9 mol) in THF (125 mL) was added dropwise to the reactionsolution slowly. Upon completion of addition, the reaction was stirredfor 10 h rising to room temperature. GC indicated a 95:5 ratio ofproduct to starting material. 500 ml of water was added to the reactionvessel and the reaction stirred overnight separating into two layers.The organic layer was isolated and the aqueous layer was extracted witht-BuOMe. The organic layers were combined and dried over MgSO₄, thenconcentrated in vacuo to yield an orange oil. The crude product wasdistilled at 129° C./0.3 mm Hg yielding 360.5 g, 91.7% yield, of a clearslightly yellow oil.

EIMS m/z 190(13; M+), 159(410, 158(39), 131(90), 130(62), 117(22),104(12), 95(57), 91(100), 77(21), 65(59); HREIMS m/z 190.0998 (C₁₂ H₁₄O₂ D -0.4 mnu); UV lmax (e) 210 (8400), 260 (230) nm; IR nmax 3027,2949, 1723, 1658, 1454, 1319, 1203, 978, 700 cm⁻¹ ; ¹ H NMR d (CDCl₃)7.15-7.3 (Ph-H5;bm), 7.00 (3-H;dt, 15.6/6.6), 5.84 (2-H;dt, 15.6/1.2),3.70 (OMe;s), 2.76 (5-H2;t, 7.2), 2.51 (4-H2; bdt, 6.6/7.2); ¹³ C NMR d(CDCl₃) 166.9 (1), 148.3(3), 140.6(Ph-1'), 128.4/128.2 (Ph2'/3'/5'6'),126.1 (Ph 4'), 121.4 (2), 51.3 (OMe), 34.2/33.8 (4/5).

Step 2. 5-phenyl-pent-2-en-1-ol ##STR26## To a 12 L 4-neck round bottomflask equipped with a thermocouple, mechanical stirrer and N₂ inlet, asolution of enoate ester (310.5 g, 1.5 mol) in THF (1.5 L) was chargedand chilled to -71° C. via a i-PrOH/CO₂ bath. To the reaction vessel,was added dropwise DIBAL (2.5 L, 1.5 M in toluene, 3.75 mol) at a rateto maintain the reaction temperature <-50° C. Upon complete addition,the reaction was stirred overnight with the reaction temperature <-50°C. TLC (3:1 Hexanes:EtOAc, SiO₂) indicated absence of starting materialafter 16 h. The reaction temperature was allowed to raise to -15° C. Thereaction was quenched slowly with 1N HCl (150 mL). At this point thereaction setup into a gelatinous solid. A spatula was employed tobreakup the the semi-solid and 1N HCl (200 mL) was added making themixture more fluid. Concentrated HCl (625 mL) was charged to form a twophase system. The layers were separated and the product extracted witht-BuOMe. The organic layer was dried over MgSO₄ and concentrated invacuo to yield a clear pale yellow oil, 247.8 g. The crude product wasdistilled at 145° C./0.25 mm Hg yielding 209.7 g, 86.2%.

EIMS m/z 162 (1:M+) 144 (16), 129 (7), 117 (9) 108 (6), 92 (17), 91(100), 75 (5), 65 (12), HREIMS m/z 162, 1049 (C₁₁ H₁₄ O, D -0.4 mmu); UVlmax (e) 206 (9900), 260 (360); IR nmax 3356, 2924, 1603, 1496, 1454,970, 746, 700 cm⁻¹ ; ¹ H NMR d 7.15-7.3 (Ph-H5;m), 5.70 (3-H;dt,15.6/6.0), 5.61 (2-H;dt, 15.6/4.8), 4.02 (1-H2;d 4.8), 2.68 (5-H2; t,7.2), 2.40 (OH;bs), 2.36(4-H2; dt, 6.0/7.2); ¹³ C NMR d141.6 (Ph 1'),131.8(3), 129.5 (2), 128.3/128.2 (Ph 2'/3'/5'/6'), 125.7 (Ph 4'), 63.3(1), 35.4/33.8 (4/5).

Step 3. (2S,3S)-2,3-Epoxy-5-phenyl-1-pentanol ##STR27## To a 1 L 3 neckround bottom flask equipped with a mechanical stirrer, thermocouple andnitrogen inlet was added CH₂ Cl₂ (350 mL), dried 4 Å molecular sieves(30 g) and L-(+)-diethyl tartrate (7.62 g, 0.037 mol). The resultingmixture was cooled to -20° C. and treated with Ti(O-i-Pr)₄ (9.2 mL,0.031 mol), followed by the addition of t-butylhydroperoxide (4.0 M inCH₂ Cl₂, 182 mL, 0.78 mol) at a rate to maintain the temperature² -20°C. Upon complete addition, the reaction mixture was stirred for another30 min, and then treated with a solution of the allylic alcohol (50 g,0.31 mol) in CH₂ Cl₂ (30 mL) at a rate to maintain the temperature² -20°C. The reaction was stirred at the same temperature for 5 h, thenfiltered into a solution of ferrous sulfate heptahydrate (132 g) andtartaric acid (40 g) in water (400 mL) at 0° C. The mixture was stirredfor 20 min, then transferred to a separatory funnel and extracted witht-BuOMe (2×200 mL). The combined organic phase was stirred with 30% NaOHsolution containing NaCl, for 1 h at 0° C. The layers were againseparated, and the aqueous phase extracted with t-BuOMe. The combinedorganic phase was washed with brine, dried over MgSO₄ and concentratedto yield 52.8 g as an amber oil.

Step 4. (2R, 3R)-2-hydroxy-3-methyl-5-phenylpentan-1-ol ##STR28## To a 5L 3 neck round bottom flask equipped with a mechanical stirrer,thermocouple and nitrogen inlet was added hexanes (1 L) and cooled to 0°C. A 2.0M solution of Me₃ Al in hexanes (800 mL, 1.6 mol) was added,followed by a solution of the epoxide (120 g, 0.677 mol) in hexanes (250mL)/CH₂ Cl₂ (50 mL) maintaining the temperature below 20° C. Uponcomplete addition, the cloudy reaction mixture was stirred at 5° C. for35 min, whereupon a solution of 10% HCl (300 mL) was added dropwise,followed by the addition of concd HCl (350 mL). The layers wereseparated, and the organic phase was washed with brine and dried overMgSO₄. After removal of the volatiles in vacuo, 122.1 gram of an oil wasobtained.

Step 5. (2R, 3R)-2-hydroxy-3-methyl-5-phenylpent-1-yl Tosylate ##STR29##To a 2 L 3 neck round bottom flask equipped with a mechanical stirrerand nitrogen inlet was added the diol (58 g, 0.30 mol), dibutyltin oxide(1.5 g, 0.006 mol, 2 mol %), toluenesulfonyl chloride (57.5 g, 0.30mol), CH₂ Cl₂ (580 mL) and triethylamine (42.0 mL, 0.30 mol). Theresulting mixture was stirred at room temperature for 2 h (although thereaction was complete within 1 h), filtered, washed with water and driedover MgSO₄. Concentration of the volatiles in vacuo afforded 104.1 gramof a slightly amber oil.

Step 6. (2R,3R)-2-[(tert-Butyldimethylsilyl)oxy]-3-methyl-5-phenylpent-1-yl Tosylate##STR30## A solution of the tosylate (100 g, 0.29 mol) and triethylamine(81.0 mL, 0.58 mol) in CH₂ Cl₂ (1200 mL) was treated with neat TBS-OTf(99 mL, 0.43 mol) dropwise with continued stirring for another 20 min.The reaction was washed twice with brine, dried over MgSO₄ andconcentrated to dryness. The oil was dissolved in a minimal amount ofhexanes and filtered over a silica pad, eluting with hexanes:EtOAc (9:1)to yield a slightly amber oil, 134 g.

Step 7. (2R,3R,5RS)-2-[(tert-Butyldimethylsilyl)oxy]-3-methyl-5-bromo-5-phenylpent-1-ylTosylate ##STR31## To a 5 L 3 neck round bottom flask equipped with amechanical stirrer, reflux condenser and nitrogen inlet was added CCl₄(1680 mL), TBS Ts (140 g, 0.30 mol), NBS (65 g, 0.365 mol) and AIBN(16.5 g, 0.10 mol). The mixture was degassed by evacuation under fullvacuum with stirring, and backfilling with nitrogen (3×). The reactionmixture was then heated to reflux, whereupon the color became darkbrown. After 15 min at vigorous reflux, the reaction mixture becamelight yellow, and chromatographic analysis indicated the reaction wascomplete. After cooling to room temperature, the reaction was filteredand the filtrate concentrated to dryness. The residue was redissolved inhexanes and filtered again, and concentrated to dryness to afford 170.3gram as an amber oil.

Step 8. (2R,3R)-2-[(tert-Butyldimethylsilyl)oxy]-3-methyl-5-phenylpent-4(E)-en-1-ylTosylate ##STR32## To a 2 L 3 neck round bottom flask equipped with amechanical stirrer, reflux condenser and nitrogen inlet was added asolution of the bromide (100 g, 0.186 mol) in acetonitrile (700 mL). DBU(83.6 mL, 0.557 mol) was added and the resulting dark brown solution wasstirred at reflux for 15 min. After cooling to room temperature, thesolvent was removed in vacuo, and the residue digested in CH₂ Cl₂ (200mL) and filtered through a silica pad. The volatiles were againevaporated, and the residue dissolved in EtOAc and washed with water,brine and dried over MgSO₄ and concentrated to dryness. Preparative mplc(Prep 500) chromatography afforded the desired unsaturated compound(50.3 g, 60% yield over 4 steps).

Step 9. (3S,4R)-3-[(tert-Butyldimethylsilyl)oxy]-4-methyl-6-phenylhex-5(E)-en-1-nitrile##STR33## The tosylate (50 g, 0.11 mol) was dissolved in DMSO (1 L) andtreated with KCN (14.2 g, 0.22 mol) and water (25 mL), and the resultingmixture was stirred at 60° C. under nitrogen for 18 h. After cooling toroom temperature, the reaction mixture was partitioned between EtOAc (1L) and water (1 L). The aqueous phase was extracted with EtOAc (500 mL),and the combined organic phase was washed with brine and dried over Na₂SO₄. Flash chromatography over silica with CH₂ Cl₂ afforded the desirednitrile in 92% yield.

Step 10. Methyl (5S,6R)-5-[(tert-Butyldimethylsilyl)oxy]-6-methyl-8-phenylocta-2(E),7(E)-dienoate##STR34## The nitrile (14.67 g, 46.5 mmol) was dissolved in toluene (200mL) and cooled to -78° C. under nitrogen. A 1.5M solution of DIBAL intoluene (37.2 mL, 55.8 mmol) was added dropwise with vigorous stirring.Upon complete addition, the cooling bath was removed and the reactionwas stirred at room temperature for 1 h. The reaction mixture wascarefully poured into 1N HCl and the mixture stirred at room temperaturefor 30 min. The layers were separated, and the organic phase was washedwith a saturated aqueous solution of sodium potassium tartrate (2×),brine and dried over Na₂ SO₄. The volatiles were removed in vacuo, andthe crude pale yellow oil was used directly in the subsequentcondensation.

The crude aldehyde from above was dissolved in THF (90 mL) and treatedwith trimethyl phosphonoacetate (9.03 mL, 55.8 mmol) andtetramethylguanidine (7.0 mL, 55.8 mmol) at room temperature undernitrogen. The reaction mixture was stirred for 16 h, then partitionedbetween EtOAc (200 mL) and water (100 mL). The aqueous phase was backextracted with EtOAc (100 mL), and the combined organic phase was washedwith water, brine and dried over Na₂ SO₄. The volatiles were removed invacuo, and the crude yellow oil (17.0 g) was chromatographed over silicagel with CH₂ Cl₂ :cyclohexane (1:1 to 2:1) to afford 13.67 grams of thedesired ester, 78.5%.

Preparation 2

(5S,6R)-5-[(tert-Butyldimethylsilyl)oxy]-6-methyl-8-phenylocta-2(E),7(E)-dienoicacid ##STR35##

Methyl (5S,6R)-5-[(tert-Butyldimethylsilyl)oxy]-6-methyl-8-phenylocta-2(E),7(E)-dienoatefrom Preparation 1, step 10 (1.00 g, 2.673 mmol) was dissolved inacetone (44 mL) and then 1N aqueous LiOH (26 mL) added at roomtemperature. The cloudy mixture was further diluted with acetone (20 mL)and the resulting yellow mixture stirred at room temperature for 23.5 h.The reaction was diluted with diethylether (400 mL) and the organicswashed with IN Hcl (l20 mL), brine (200 mL) and H₂ O (160 mL). Theorganics were dried (MgSO₄) and concentrated in vacuo to leave a yellowoil which was purified by column chromatography (gradient elution: 5%AcOH+20%-40% EtOAc/Hexanes) to give carboxylic acid as a yellow oil (960mg, 100%).

[a]_(D) ⁵⁸⁹ +87.6° (c 10.5, CHCl₃); ¹ H NMR (CDCl₃) d 7.38-7.19 (m,PhH₅), 7.09 (ddd, J=15.2, 7.6 and 7.9 Hz, 3-H), 6.38 (d, J=16 Hz, 8-H),6.16 (dd, J=16 and 8 Hz, 7-H), 5.85 (d, J=15.8 Hz, 2-H), 3.81-3.75 (m,5-H), 2.49-2.37 (m, 6-H, 4-HH'), 1.12 (d, J=6.7 Hz, 6-Me), 0.91 (s, 9H,SiCMe₃), 0.065 (s, SiMe), 0.068 (s, SiMe) ppm; IR (CHCl₃) l_(max) 2957,2930, 2858, 1697, 1258, 1098, 838 cm⁻¹ ; MS (FD) 360.2 (M+,100); Anal.calcd. for C₂₁ H₃₂ O₃ requires: C,69.95; H,8.95%. Found: C,69.19;H,8.39%.

Preparation 3 ##STR36##

To a stirred solution of the carboxylic acid of Preparation 2 (720 mg, 2mmol) in dry dimethylformamide (5.50 mL) was added1-Ethyl-3-(3-dimethyaminopropyl)carbodiimide (459 mg, 2.4 mmol) andN-hydroxy-succinimide (299 mg, 2.6 mmol) at room temperature. Themixture was stirred for 28 h and then diluted with EtOAc (100 mL) andwashed with 1N aqueous HCl (2×50 mL), H₂ O (75 mL), dried (MgSO4) andconcentrated in vacuo to leave an oil. Crude product was purified bycolumn chromatography (gradient elution: 5-30% EtOAc/Hexanes) to giveactive ester as a pale yellow oil (724 mg,80%).

[a]_(D) ⁵⁸⁹ +71.3° (c 10.1, CHCl₃); ¹ H NMR (CDCl₃) d 7.36-7.20 (m,PhH₅, 3-H), 6.38 (d,J=16 Hz, 8-H), 6.14 (dd, J=16.1 and 8.0 Hz, 7-H),6.03 (d, J=16 Hz, 2-H), 3.79 (q, J=4.3 Hz, 5-H), 2.94 (brs, CH₂ CH₂),2.58-2.42 (m, 6-H, 4-HH'), 1.10 (d,J=6.8 Hz, 6-Me), 0.90 (s, 9H,SiCMe₃), 0.05 (s, 6H, SiMe₂) ppm; IR (CHCl₃) l_(max) 2957, 2931, 2858,1772, 1741, 1648, 1364, 1254, 1092, 1069, 838 cm⁻¹ ; MS (FD) 457(M+,100); Anal. calcd. for C₂₅ H₃₅ NO₅ requires: C,65.61;H,7.71;N,3.06%.Found: C,65.51;H,7.56; N, 3.02%.

Preparation 4 ##STR37##

To a stirred solution of active ester of Preparation 3 (2.50 g,5.47mmol) in CH₃ CN (130 mL) was added 48% aqueous HF (15 mL) at 0 C. Thesolution was stirred at 0 C. for 0.75 h and then at room temperature for4 h. The reaction was diluted with diethylether (300 mL) and washed withH₂ O until the wash was ˜pH7. Organics were dried (MgSO₄) andconcentrated in vacuo to give a yellow residue which was recrystallizedfrom Et2O to give alcohol as white crystals (1.46 g,78%). ¹ H NMR(CDCl₃) d 7.41-7.20 (m,PhH₅,3-H), 6.48 (d,J=16 Hz,8-H), 6.15-6.07(m,7-H,2-H), 3.71-3.65 (m,5-H), 2.83 (brs,CH₂ CH₂), 2.60-2.33(m,6-H,4-CH₂),1.95 (brs, 5-OH), 1.14 (d,J=6.8 Hz,6-Me) ppm; IR u (KBr)3457,1804,1773,1735,1724,1209,1099,1067,1049,975, 744,694 cm⁻¹ ; UV(EtOH) l_(max) 250 (e=20535) nm; MS (FD) 343.2 (M⁺,100); [a]_(D) -57.8°(c 10.56, CHCl₃); Anal. calcd. for C₁₉ H₂₁ NO₅ S requires:C,66.46;H,6.16;N,4.08%. Found: C,66.49; H,6.16; N, 4.07%.

Preparation 5 ##STR38##

Acetone (10 mL) was added to a solution of the active ester of Procedure3 (2.90 g, 6.35 mmol) in dichloromethane (20 mL) and the solution cooledto 0° C. An aqueous solution of oxone (11.7 g, 19 mmol) in H₂ O (30 mL)was slowly added to stirred solution of aqueous NaHCO₃ (5.3 g, 63.5mmol) in H₂ O (30 mL) (gas evolution observed!). The resulting solutionwas added to the reaction mixture and stirred at 0° C. for 7 h (tlc- 50%conversion). Further oxone (6 g) and acetone (15 mL) were added and themixture stirred for 1.5 h (tlc- all SM consumed). The reaction mixturewas diluted with H₂ O (5 volumes) and product extracted with CH₂ Cl₂(5×100 mL). Combined, dried (MgSO₄) organics were concentrated in vacuoto give product as a yellow gummy solid (2.88 g). Tlc and ¹ H NMRindicated 90% desired epoxide product (a:b=1:1.62): 10% SM. Crudeproduct was purified by column chromatography (SiO₂ :gradientelution:15%-25% EtOAc:Hexanes) to give recovered styrene (389 mg, 13%)and epoxide as a yellow oil (2.38 g, 80%). Epoxides (2 g, a:b=1:1.50)were separated by HPLC to give b-epoxide as a white crystalline solid(1.17 g, 59%. 99.8% ee) and a-epoxide as white crystalline solid (0.864g, 43.2%, 99% ee).

Preparation 6 ##STR39## HPLC: C18 reverse phase, flow rate 1 mL/min,60:40-CH₃ CN:H₂ O, l=254 nm, b-epoxide Rt=17.2 mins (AUC 1.5); [a]_(D)⁵⁸⁹ +77.36 (c 1.06, CH₂ Cl₂); ¹ H NMR (CDCl₃) d 7.35-7.24 (m, 6H, ArH₅,3-H), 6.08 (d, J=15.8 Hz, 2-H), 3.91-3.88 (m, 5-H), 3.70 (s, 8-H), 2.97(dd, J=6 and 0.9 Hz, 7-H), 2.85 (s, 4H, CH₂ CH₂), 2.56-2.51 (m, 4-HH'),1.78-1.76 (m, 6-H), 1.06 (d, J=6.9 Hz, 6-Me), 0.86 (s, 6H, SiCMe₃), 0.05(s, SiMe), 0.01 (s, SiMe) ppm; IR (CHCl₃) u 2957, 2931, 1742, 1773,1200, 1069, 839 cm⁻¹ ; UV (EtOH) l_(max) 217 (e=21180) nm; MS (FD) m/z474 (M⁺, 10), 416 ([M-CMe₃ ]⁺, 100); Anal. calcd. for C₂₅ H₃₅ NO₆requires: C, 63.40; H, 7.45; N, 2.96%. Found: C, 63.45; H, 7.31; N,3.21%. Preparation 7 ##STR40## HPLC: C18 reverse phase, flow rate 1mL/min, 60:40-CH₃ CN:H₂ O, l=254 nm, a-epoxide Rt=21.0 mins (AUC 1.0);[a]_(D) ⁵⁸⁹ +10.68° (c 1.03, CH₂ Cl₂); ¹ H NMR (CDCl₃) d 7.38-7.26 (m,6H, ArH₅, 3-H), 6.13 (d, J=15.7 Hz, 2-H), 3.94-3.89 (m, 5-H), 3.60 (s,8-H), 2.99 (dd, J=7.3 and 1.3 Hz, 7-H), 2.85 (s, 4H, CH₂ CH₂), 2.76-2.71(m, 4-H), 2.61-2.54 (m, 4-H'), 1.64 (dt, J=7.2 and 2.8 Hz, 6-H), 1.03(d, J=7 Hz, 6-Me), 0.90 (s, 9H, SiMe₃), 0.08 (s, SiMe), 0.05 (s, SiMe)ppm; IR (CHCl₃) u 2957, 2931, 1741, 1773, 1649, 1254, 1200, 1125, 1095,1069, 891, 839 cm⁻¹ ; UV (EtOH) l_(max) 218 (e=21727) nm; MS (FD) m/z474 (M⁺, 10), 416 ([M-CMe₃ ]⁺, 100); Anal. calcd. for C₂₅ H₃₅ NO₆requires: C, 63.40; H, 7.45; N, 2.96%. Found: C, 63.20; H, 7.63; N,3.07%. Preparation 8 ##STR41## Preparation of β-Epoxy Fragment A Acid

A solution of 2a' (1.91 g, 5.30 mmol) of the formula ##STR42## in CH₂Cl₂ (18 mL) was treated with m-chloroperbenzoic acid (0.96 g, 5.6 mmol)and the mixture stirred for 4 h before the volatiles were evaporated togive a colorless oil (2.88 g). Preparative HPLC was used to separate theepoxides (1.2:1 β:α) to give the desired β-epoxide as a colorless solid(42%). ¹ H NMR (500 MHz, CDCl₃) δ 7.37-7.27 (m, 5H), 7.11 (ddd, 1H,J=15.5, 7.6, 7.6 Hz), 5.92 (d, 1H, J=15.5 Hz), 3.90 (ddd, 1H, J=5.6,5.6, 5.4 Hz), 3.70 (d, 1H, J=2.0 Hz), 3.00 (dd, 1H, J=6.6, 2.1 Hz), 2.51(dd, 2H, J=6.5, 6.5 Hz), 1.77-1.73 (m, 1H), 1.10 (d, 3H, J=6.8 Hz), 0.89(s, 9H), 0.07 (s, 3H), 0.03 (s, 3H). MS (FD) m/z 377 (M+1, 43), 319(M-57, 100).

Preparation 9 ##STR43## Alternate Preparation of β-Epoxy Fragment A Acid

To a stirred solution of acid 2a' (100 mg, 0.277 mmol) in CH₃ CN (3.7mL) at 0° C. was added a solution of Na₂ EDTA (1×10⁻⁴ M in H₂ O, 2.8 mL,0.28 μmol) and tetrabutylammonium hydroxide (1 M in MeOH, 28 μL, 28μmol). After NaHCO₃ (23.3 mg, 0.277 mmol) was added, the pH was adjustedto 8.0 with 2 M NaOH and a mixture of Oxone (1.70 g, 2.77 mmol) andNaHCO₃ (722 mg, 8.59 mmol) prepared. A 100 mg portion of theOxone/NaHCO₃ was added followed by ketone (7) (143 mg, 0.554 mmol). ThepH was immediately adjusted to 7.8-8.0 with 2 M NaOH. The rest of theOxone/NaHCO₃ mixture was added in 95 mg portions in 10 min intervals anda solution of (7) (143 mg, 0.554 mmol) in CH₃ CN (500 μL) was added tothe mixture during this period via a syringe pump. Throughout theexperiment the pH was maintained at 7.8-8.0 with 2 M NaOH and 1 N H₂SO₄. HPLC analysis (C18 reverse phase, detection at 220 nm, flow rate at1 mL/min, CH₃ CN (0.05% TFA)/H₂ O (0.05% TFA)-% CH₃ CN: 80% to 90% over10 min) 3 h after the Oxone addition revealed that the conversion wasgreater than 95% with a β/α epoxide ratio of 5.0:1. The mixture wasfiltered and the wetcake washed with CH₂ Cl₂ (15 mL). The filtrate waswashed with H₂ O (15 mL) and the aqueous phase back extracted with CH₂Cl₂ (15 mL). The combined organic phases were washed with 0.1 M HCl (10mL) and H₂ O (10 mL), dried (MgSO₄), and concentrated to give the crudeproduct as a yellow oil (104 mg, 100%).

Preparation 10 ##STR44## Alternate Preparation of β-Epoxy Fragment AN-Hydroxysuccinimide Ester

The epoxidation of N-hydroxysuccinimide ester of Preparation 3 (127 mg,0.277 mmol) was performed in the same manner as described in Preparation9 except that the pH was lowered to 5.6 with 1 N H₂ SO₄ after thetetrabutylammonium hydroxide was added, prior to addition of sodiumbicarbonate. HPLC analysis (same method as used for the analysis used inPreparation 9) 3.5 h after the Oxone addition revealed that theconversion was greater than 95% with a β/α epoxide ratio of 6.3:1. AfterCH₂ Cl₂ (6 mL) was added, the mixture was filtered and the wetcakewashed with CH₂ Cl₂ (14 mL). The filtrate was washed with H₂ O (10 mL)and the aqueous phase back extracted with CH₂ Cl₂ (2×20 mL). Thecombined organic phases were dried (MgSO₄) and concentrated to acolorless oil. Chromatography on silica gel with EtOAc/hexane (1:3) gavethe title compound as colorless solid (8:1 β/α epoxide mixture, 82 mg,63%).

Preparation 11 ##STR45## Preparation of β-Epoxy Fragment A Methyl Ester

The epoxidation of the methyl ester of Preparation 1, step 10 (104 mg,0.278 mmol) was performed in the same manner as described in Preparation9 except that the pH was lowered to 3.3 with 1 N H₂ SO₄ after thetetrabutylammonium hydroxide was added, prior to the addition of sodiumbicarbonate. HPLC analysis (same method as used for the analysis of theproduct of Preparation 9 except % CH₃ CN: 95%, isocratic) 2 h after theOxone addition revealed that conversion was greater than 95% with a β/αepoxide ratio of 4.9:1. After CH₂ Cl₂ (6 mL) was added, the mixture wasfiltered and the wetcake washed with CH₂ Cl₂ (14 mL). The filtrate waswashed with H₂ O (10 mL) and the aqueous phase back extracted with CH₂Cl₂ (2×20 mL). The combined organic phases were dried (MgSO₄) andconcentrated to give the crude product as a yellow oil (123 mg, 113%). ¹H NMR (500 MHz, CDCl₃) δ 7.38-7.26 (m, 5H), 6.99 (ddd, 1H, J=15.8, 7.6,7.6 Hz), 5.91 (d, 1H, J=15.8 Hz), 3.87 (ddd, 1H, J=5.6, 5.6, 5.4 Hz),3.75 (s, 3H), 3.70 (d, 1H, J=2.1 Hz), 3.00 (dd, 1H, J=6.8, 2.1 Hz),2.49-2.45 (m, 2H), 1.75-1.69 (m, 1H), 1.10 (d, 3H, J=6.8 Hz), 0.88 (s,9H), 0.06 (s, 3H), 0.02 (s, 3H). MS (FD) m/z 391 (M+1, 8), 333 (M-57,100).

Preparation 12 ##STR46## Boc amine (1.69 g,5.09 mmols) of the formula##STR47##

PCT Intnl. Publ. No. WO 97/07798, published Mar. 6, 1997; was dissolvedin trifluoroacetic acid (17 ml) and the solution stirred at roomtemperature under a dry nitrogen atmosphere for 4.75 h and thenconcentrated in vacuo and dried under high vacuum for 24 h to give theamine salt as a yellow viscous oil (1.76 g, 100%).

[α]_(D) ⁵⁸⁹ -11.54° (c 1.04, MeOH); ¹ H NMR (CDCl₃) δ Unit C': 7.43 (brs, 3H, NH₃ ⁺),3.34-3.28 (m, 3-H), 3.18-3.12 (m, 3-H'), 1.42 (s, 2-Me),1.36 (s, 2-Me); Unit D: 10.94 (br s, CO₂ H), 5.23-5.20 (m,2-H),1.92-1.77 (m, 3H, 3-HH', 4-H), 1.10 (d, J=5.8 Hz, 5-H₃), 0.98 (d,J=5.8 Hz, 4-Me) ppm; IR (CHCl₃) ν 2963, 1746, 1710, 1678, 1192, 1172cm⁻¹ ; MS (FAB) 232.2 ([M+1]⁺, 100).

Preparation 13 ##STR48##

To a stirred solution of amine salt of Preparation 12 (5.09 mmols) indioxane (20 mL) was added sodium bicarbonate (2.14 g,25.5 mmols)followed by FmocCl (1.58 g,6.11 mmols) at room temperature. The mixturewas diluted with H₂ O (4 mL) and stirred for 19 h. The reaction mixturewas quenched in 1N aqueous HCl (150 mL) and extracted with EtOAc (2×100mL). Combined organics were washed with H₂ O (100 mL), dried (MgSO₄) andconcentrated in vacuo to give a yellow gummy solid. The crude productwas purified by column chromatography (Biotage-SiO₂ : gradient elution;10%-75% EtOAC: Hexanes) to provide Fmoc amine as a pale yellow solid(850 mg, 37%). Product was contaminated with amino acid, which wasremoved by dissolving the product in EtOAc and stirring with 1N HCl aqfor several hours. Organics were dried and concentrated to give product(85:15 product: amino acid).

[α]_(D) ⁵⁸⁹ -15.95° (c 0.50, CH₂ Cl₂); ¹ H NMR (CDCl₃) δ Unit C': 7.59(d, J=7.4 Hz, ArH₂), 7.67-7.61 (m, ArH₂), 7.43 (t, J=7.3 Hz, ArH₂),7.36-7.30 (m, ArH₂), 5.88 (t, J=5.8 Hz, NH), 4.41-4.38 (m, 3'-HH'),4.35-4.28 (m,4'-H), 3.42 (d, J=6.5 Hz, 3-HH'), 1.27 (s, 2Me), 1.26 (s,2-Me); Unit D: 8.40 (br s, CO2H), 5.18-5.13 (m, 2-H), 1.87-1.69 (m, 3H,3-HH', 4-H), 0.97 (d, J=5,8 Hz, 5-H3), 0.93 (d, J=6.1 Hz, 4-Me) ppm; IR(KBr) ν 2959, 2937, 1730, 1540, 1471, 1451, 1307, 1268, 1145, 1128, 759,741 cm⁻¹ ; UV (EtOH) λ_(max) 299 (e=5851), 288 (e=4773), 265 (e=18369),227 (e=4813) nm; MS (FAB) 454 ([M+1]⁺, 26); Anal. calcd. for C₂₆ H₃₁ NO₆requires: C, 68.86; H, 6.89; N, 3.09%. Found: C, 68.92; H, 7.01; N,3.34%.

Preparation 14 ##STR49## Preparation of Fmoc Seco

To a mixture of a fragment A-B compound (4') ##STR50## (600 mg, 1.01mmol, Barrow, R. A. et al., J. Am. Chem. Soc. 117, 2479-2490 (1995)), acompound of Preparation 13 (618 mg, 1.36 mmol), and DMAP (24.7 mg, 0.202mmol) in CH₂ Cl₂ (3.6 mL) at 0° C. was added a solution of DCC (281 mg,1.36 mmol) in CH₂ Cl₂ (1.2 mL) and the reaction was allowed to stir 5min at 0° C. and 30 min at rt. After the mixture was diluted withEtOAc/hexane (1:1, 15 mL), it was filtered through Celite and the cakewashed with EtOAc/hexane (1:1, 15 mL). The filtrate was washed with 1 MHCl (10 mL), saturated NaHCO₃ solution (10 mL), brine (10 mL), dried(MgSO₄), and concentrated to a yellow foam. Chromatography on silica gelwith EtOAc/hexane (1:2.5 to 1:1) gave the title compound as a colorlessfoam (864 mg, 83.5%). ¹ H NMR (500 MHz, CDCl₃) δ 7.78 (d, 2H, J=7.5 Hz),7.69-7.66 (m, 2H), 7.40 (dd, 2H, J=7.5, 7.4 Hz), 7.34-7.22 (m, 7H), 7.19(d, 1H, J=1.8 Hz), 7.05 (dd, 1H, J=8.5, 1.8 Hz), 6.86-6.80 (m, 1H), 6.82(d, 1H, J=8.4 Hz), 6.45 (d, 1H, J=8.4 Hz), 6.44 (d, 1H, J=15.5 Hz),6.11-6.03 (m, 2H), 5.91 (d, 1H, J=15.7 Hz), 5.18 (m, 1H), 5.08-5.01 (m,2H), 4.77 and 4.67 (AB quartet, 2H, J=11.9 Hz), 4.43-4.33 (m, 2H), 4.27(dd, 1H, J=7.4, 7.2 Hz), 3.86 (s, 3 H), 3.43 (d, 2H, J=6.6 Hz), 3.21(dd, 1H, J=14.1, 5.7 Hz), 3.07 (dd, 1H, J=14.2, 6.7 Hz), 2.69-2.58 (m,3H), 1.79-1.72 (m, 2H), 1.67-1.61 (m, 1H), 1.29 (s, 3H), 1.20 (s, 3H),1.17 (d, 3H, J=6.8 Hz), 0.91 (d, 3H, J=6.4 Hz), 0.87 (d, 3H, J=6.4 Hz).Anal. Calcd for C₅₃ H₅₈ Cl₄ N₂ O₁₀ : C, 62.11; H, 5.70; N, 2.73. Found:C, 62.21; H, 5.68; N, 2.50.

EXAMPLE 1 ##STR51## Preparation of β-Epoxy Fragment A-B

The epoxidation of fragment A-B of formula (4') (653 mg, 1.11 mmol,Barrow, R. A. et al., J. Am. Chem. Soc. 117, 2479-2490 (1995)) wasperformed in the same manner as described in Procedure 9 except that thepH was lowered to 4.4 with 1 N H₂ SO₄ after the tetrabutylammoniumhydroxide was added, prior to addition of sodium bicarbonate. Thereaction was complete before all of the Oxone/NaHCO₃ mixture and ketonewere added. HPLC analysis (same method as used for the analysis of theproduct of Procedure 9 except % CH₃ CN: 70% to 85% over 15 min) revealedthat the Fragment A-B starting material was consumed to give a 5:1 β/αepoxide mixture after 80% of the Oxone/NaHCO₃ mixture had been added(1.6 equivalents of the 2 equivalents of (7) which were added slowly hadbeen added). After CH₂ Cl₂ (24 mL) was added, the mixture was filteredand the wetcake washed with CH₂ Cl₂ (56 mL). The filtrate was washedwith H₂ O (40 mL) and the aqueous phase back extracted with CH₂ Cl₂(2×40 mL). The combined organic phases were dried (MgSO₄) andconcentrated to give the crude product as a light yellow foam (798 mg,119%), which was used directly in the next reaction withoutpurification. ¹ H NMR (500 MHz, CDCl₃) δ 7.39-7.29 (m, 5H), 7.21 (d, 1H,J=2.2 Hz), 7.06 (dd, 1H, J=8.4, 2.1 Hz), 6.93 (ddd, 1H, J=15.4, 7.4, 7.4Hz), 6.88 (d, 1H, J=8.4 Hz), 5.94 (d, 1H, J=15.4 Hz), 5.90 (d, 1H, J=7.8Hz), 5.09 (ddd, 1H, J=7.7, 6.0, 5.9 Hz), 4.82 and 4.76 (AB quartet, 2H,J=11.8 Hz), 3.90 (s, 3H), 3.83 (d, 1H, J=2.1 Hz), 3.78-3.74 (m, 1H),3.25 (dd, 1H, J=14.2, 5.9 Hz), 3.15 (dd, 1H, J=14.2, 6.0 Hz), 3.02 (dd,1H, J=6.7, 2.1 Hz), 2.58-2.52 (br m, 1H), 2.39 (ddd, 1H, J=14.8, 7.6,7.6 Hz), 1.79 (m, 1H), 1.14 (d, 3H, J=6.9 Hz). MS (FD) m/z 603 (M⁺).

Example 2 ##STR52## Preparation of β-Epoxy Fmoc Seco from Fmoc Seco

To a stirred solution of a compound of Preparation 14 (382 mg, 0.373mmol) in CH₃ CN (4.7 mL) at 0° C. was added a solution of Na₂ EDTA(1×10⁻⁴ M in H₂ O, 3.7 mL, 0.37 μmol) and tetrabutylammonium hydroxide(1 M in MeOH, 37 μL, 37 μmol). The pH was lowered to 3-6 with 1 N H₂ SO₄before NaHCO₃ (31.3 mg, 0.373 mmol) was added. After a mixture of Oxone(2.29 g, 3.72 mmol) and NaHCO₃ (975 mg, 11.6 mmol) was prepared, the pHwas adjusted to 8.2 with 1 N H₂ SO₄ and the ketone (7) (385 mg, 1.49mmol) added. The Oxone/NaHCO₃ mixture was then added in 128 mg portionsin 10 min intervals and the pH maintained at 7.8-8.2 with 2 M NaOH and 1N H₂ SO₄. HPLC analysis (same method as used for the analysis of theproduct of Procedure 9 except % CH₃ CN: 95%, isocratic) 1 h after theOxone addition revealed that the conversion was 85% with a β/α epoxideratio of 9.5:1. After CH₂ Cl₂ (8 mL) was added, the mixture was filteredand the wetcake washed with CH₂ Cl₂ (19 mL). The filtrate was washedwith H₂ O (13 mL) and the aqueous phase back extracted with CH₂ Cl₂(2×27 mL). The combined organic phases were dried (MgSO₄) andconcentrated to give the crude product as a beige foam (375 mg, 97%).

Example 3 ##STR53## Preparation of β-Epoxy Fmoc Seco from β-EpoxyFragment A-B

A solution of the epoxide product of Example 1 (788 mg, 1.09 mmoltheory) in CH₂ Cl₂ (3.7 mL) was added to the acid of Preparation 13 (742mg, 1.64 mmol) followed by DMAP (26.6 mg, 0.218 mmol), and the mixturewas immediately cooled to 0° C. After a solution of DCC (338 mg, 1.64mmol) in CH₂ Cl₂ (1.2 mL) was added, the mixture was allowed to stir for5 min at 0° C. and for 1 h at rt. The mixture was then diluted withEtOAc/hexane (1:1, 20 mL), filtered through Celite, and concentrated toa yellow foam. Chromatography on silica gel with EtOAc/hexane (1:3 to1:2) gave the title compound as a light yellow foam (7.8:1 β/α epoxidemixture, 772 mg, 68% from Fragment A-B corrected to 55% due tocontamination by byproduct). ¹ H NMR (500 MHz, CDCl₃) δ 7.77 (d, 2H,J=7.5 Hz), 7.66-7.60 (m, 2H), 7.40-7.24 (m, 9H), 7.19 (s, 1H), 7.05 (d,1H, 8.4 Hz), 6.86-6.79 (m, 1H), 6.82 (d, 1H, J=8.4 Hz), 6.44 (d, 1H,J=8.0 Hz), 5.98-5.94 (br m, 1 H), 5.91 (d, 1H, J=15.6 Hz), 5.23-5.20 (m,1H), 5.09-5.04 (m, 1H), 5.0 (dd, 1H, J=9.8, 3.2 Hz), 4.77 and 4.68 (ABquartet, 2H, J=11.8 Hz), 4.43-4.34 (m, 2H), 4.27-4.23 (m, 1H), 3.85 (s,3H), 3.73 (d, 1H, J=1.7 Hz), 3.44-3.38 (m, 2H), 3.20 (dd, 1H, J=14.2,5.7 Hz), 3.07 (dd, 1H, J=14.2, 6.7 Hz), 2.94 (dd, 1H, J=6.9, 1.7 Hz),2.66-2.57 (m, 2H), 1.97-1.90 (m, 1H), 1.80-1.71 (m, 2H), 1.60-1.55 (m,1H), 1.25 (s, 3H), 1.19 (s, 3H), 1.15 (d, 3H, J=6.9 Hz), 0.93 (d, 6H,J=6.4 Hz), MS (FD) m/z 1038 (M⁺).

Example 4 ##STR54## Preparation of β-Epoxy Fmoc Seco from Fragment A-B:Epoxidation at pH 10.5 followed by coupling with preactivation of FmocC'D Acid

Epoxidation: To a stirred mixture of fragment A-B (4') (650 mg, 1.10mmol), sodium tetraborate buffer (0.05 M in 4×10⁻⁴ M aqueous Na₂ EDTA,11.2 mL), tetrabutylammonium hydrogen sulfate (14.9 mg, 43.9 μmol), andketone (7) (568 mg, 2.20 mmol) in CH₃ CN (16.8 mL) at 0° C. was added asolution of Oxone (2.61 g, 4.24 mol) in aqueous Na₂ EDTA (4×10⁻⁴ M, 20mL) and a solution of K₂ CO₃ (0.89 M, 20 mL) over 2 h. HPLC analysis(same method as used for the analysis of the product of Preparation 9except % CH₃ CN: 70% to 85% over 15 min) at the end of the additionrevealed that the conversion was >95% with a β/α epoxide ratio of 6.5:1.The mixture was diluted with CH₂ Cl₂ (30 mL) and washed with H₂ O (20mL). The aqueous layer was back extracted with CH₂ Cl₂ (2×30 mL) and thecombined organic layers were dried (MgSO₄) and concentrated to faintyellow foam (995 mg) which was taken into the next step without furtherpurification. Coupling: To a solution of the acid (10a) (723 mg, 1.60mmol) and DMAP (26.9 mg, 0.220 mmol) in CH₂ Cl₂ (1.7 mL) at 0° C. wasadd a solution of the DCC in CH₂ Cl₂ (1.3 mL). After the mixture wasstirred for 5 min, a solution of the crude alcohol in CH₂ Cl₂ (1.5 mL)was added and the reaction was stirred for 5 min at 0° C. and 1 h at rt.The mixture was then diluted with EtOAc/hexane (1:1, 20 mL), filteredthrough Celite, and concentrated to a yellow foam. Chromatography onsilica gel with EtOAc/hexane (1:3 to 1:2) gave the title compound as alight yellow foam (10.3:1 β/α epoxide mixture, 820 mg, 71% contaminatedwith only 4% of byproduct).

Example 5 ##STR55## Preparation of Cryptophycin 52 from Cryptophycin 51

The epoxidation of Cryptophycin 51 (181 mg, 0.277 mmol) was performed inthe same manner as described in Preparation 9 except that the pH waslowered to 7.8 with 1 N H₂ SO₄ after the tetrabutylammonium hydroxidewas added, prior to addition of sodium bicarbonate. HPLC analysis (samemethod as used for the analysis of the product of Preparation 9 except %CH₃ CN: 60% to 90% over 20 min) near the end of the Oxone additionrevealed that the conversion was less than 10% with a β/α epoxide ratioof 5-7:1.

Example 6 ##STR56## Preparation of Cryptophycin 52 from β-Epoxy FmocSeco

To a solution of β-Epoxy Fmoc Seco of Example 3 (767 mg, 0.737 mmolcorrected to 0.54 mmol due to contamination by α-epoxide and byproduct)in DMF (74 mL) was added piperidine (364 μL, 3.69 mmol), and thereaction was allow to stir for 20 h before it was diluted with EtOAc(200 mL) and washed with H₂ O (3×200 mL). The combined aqueous layerswere back extracted with EtOAc (60 mL) and the combined organic layersdried (MgSO₄) and concentrated to an orange oil. Crystallization fromtoluene (2.5 mL, seeded with Cryptophycin 52) provided the titlecompound as a colorless solid (171 mg, 47%).

Example 7 ##STR57##

To a solution of β-epoxide of Preparation 6 (473 mg, 1.0 mmol) in dryDMF (6.7 mL) was added amino acid "B" (459 mg, 2.0 mmols), representedby the formula ##STR58##

PCT Intnl. Publ. No. WO 97/07798, published Mar. 6, 1997; followed byN,O-bis-(trimethylsilyl)acetamide (618 uL, 2.5 mmols) at roomtemperature under a nitrogen atmosphere. The resulting mixture washeated at 55° C. (solution formed) for 8 h, diluted with EtOAc (250 mL)and washed with 1N aqueous HCl (3×80 mL), H₂ O (100 mL). Combined, dried(MgSO₄) organics were concentrated in vacuo to give a yellow foam (590mg), which further purified by column chromatography (SiO₂, gradientelution; CH₂ Cl₂ -5%-10% MeOH: CH₂ Cl₂) to give silyl ether product aswhite foam (489 mg, 89%).

[α]_(D) ⁵⁸⁹ +28.33° (c 1.06, MeOH); ¹ H NMR (DMSO-d6) δ Unit A:7.33-7.17 (m, ArH₅), 6.55-6.40 (m, 3-H), 6.03 (d, J=15.3 Hz, 2-H),3.83-3.76 (m, 5-H), 3.71 (s, 8-H), 2.90 (d, J=6.8 Hz, 7-H), 2.46-2.27(m, 4-HH'), 1.50-1.44 (m, 6-H), 0.94 (d, J=6.7 Hz, 6-Me), 0.74 (s, 9H,SiMe₃), -0.54 (s, SiMe), -0.13 (s, SiMe); Unit B: 7.76 (d, J=7.3, NH),7.33-7.17 m, ArH), 7.04 (d, J=8.5, ArH), 6.90 (d, J=8.5, ArH), 4.27-4.23(m, 2-H), 3.72 (s, 3H, OMe), 3.02 (dd, J=13.3 and 4.3 Hz, 3-H), 2.78(dd, J=13.5 and 7.8 Hz, 3-H') ppm; IR (KBr) u 2955, 2930, 2857, 1668,1605, 1504, 1463, 1454, 1279, 1258, 1067, 1026, 837, 776 cm⁻¹ ; UV(EtOH) l_(max) 278 (e=2219) nm.

Example 8 ##STR59## Method A

To a solution of silyl ether of Example 7 (160 mg, 0.272 mmols) in dryDMF (3.5mL) was added sodium bicarbonate (228 mg, 2.72 mmols) followedby solid tetrabutylammonium fluoride-hydrate (TBAF)(358 mg, 1.36 mmols).The mixture was heated at 60° C. for 17 h and then further TBAF (358 mg,1.36 mmols) and heated for 9 h and finally a solution of 1M TBAF in THF(360 uL, 1.36 mmols) added turning the reaction a brown color. Themixture was heated for 20 mins and then the reaction quenched in water(100 mL) and extracted with EtOAc (3×50 mL). Combined, dried (Na₂ SO₄)organics were concentrated in vacuo to give a brown oily gum (248 mg).Crude carboxylate salt was used in the next step without furtherpurification.

Example 9 ##STR60## Method B

To a solution of silyl ether of Example 7 (145 mg, 0.247 mmols) in drytetrahydrofuran (3.0 mL) was added a 1M solution of tetrabutylammoniumfluoride (800 uL, 0.8 mmols) under a dry nitrogen atmosphere. Theresulting solution was heated at 60° C. for 7 h and then worked-up asdescribed above to give a brown residue (166 mg, 94%). Crude carboxylatesalt was used in the next step without further purification.

Example 10 ##STR61##

To a dry solution of crude carboxylate salt (0.272 mmols) in DMSO (3.5mL) was sodium bicarbonate (274 mg, 3.26 mmols) followed by slowaddition of a solution of t-butyl bromide (373 mg, 2.72 mmols) in DMSO(1.5 mL) over ˜2 h at room temperature and under nitrogen. The mixturewas stirred for a further 21 h and then quenched in brine (50 mL) andextracted with EtOAc (3×30 mL). Combined organics were washed with water(50 mL), dried (Na₂ SO₄) and concentrated in vacuo to give crude esteras a gummy solid (117 mg, 81%). The crude alcohol A-B was used in thenext step without further purification.

Example 11 ##STR62##

To a stirred solution of carboxylic acid D-C' of Preparation 13 (129 mg,0.285 mmols) in dry dichloromethane (1.0 mL) was added DMAP (5.4 mg,0.044 mmols) and DCC (59 mg, 0.285 mmols) at room temperature under adry nitrogen atmosphere. The solution was stirred for 0.5 h and thensolid sodium bicarbonate (37 mg, 0.44 mmols) added followed by asolution of crude alcohol A-B of Example 10 (117 mg, 0.22 mmols) in drydichloromethane (1.2 mL). A precipitate formed within 10 mins and themixture was stirred for a further 50 mins. The crude reaction mixturewas directly applied onto a SiO₂ column and purified (gradient elution;10%-40% EtOAc:Hexanes) to give methyl sulphide product as pale yellowsolid (122 mg, 46% over 3 steps).

¹ H NMR (CDCl₃) δ Unit A: 7.43-7.20 (m, ArH₅), 6.90-6.81 (m, 2H, 3-H,ArH), 5.93 (d, J=15.6 Hz, 2-H), 5.14-4.93 (m, 5-H), 3.05 (dd, J=14.5 and8.3 Hz, 7-H), 2.65-2.63 (m, 4-HH'), 2.00-1.95 (m, 6-H), 1.17 (d, J=7.0,6-Me); Unit B: 7.43-7.20 (m, ArH), 7.06 (d, J=8.1 Hz, ArH), 6.90-6.81(m, ArH), 6.44 (d, J=7.7 Hz, NH), 5.19 (q, J_(AB) =11.8 Hz, 1'-HH),5.14-4.93 (m, 2-H), 3.87 (s, OMe), 3.20-3.10 (m, 3-HH'), 2.21 (s, SMe);Unit C': 7.79 (d, J=7.4 Hz, ArH₂), 7.67 (d, J=6.9 Hz, ArH₂), 7.43-7.20(m, ArH₄), 6.04 (d, J=7.7 Hz, NH), 4.42-4.34 (m, 3'-HH'), 4.30-4.25 (m,4'-H, 3.42 (d, J=6.2 Hz, 3-HH'), 1.27 (s, 2-Me), 1.20 (s, 2-Me); Unit D:5.22-5.18 (m, 2-H), 1.82-1.58 (m, 3H, 3-HH',4-H), 0.96 (s, 5-H3), 0.94(s, 4-Me) ppm.

Example 12 ##STR63##

To a stirred solution of methyl sulphide of Example 11 (56 mg,0.058mmols) in acetone (10 mL) was added sodium bicarbonate (64 mg, 0.764mmols) followed by an aqueous solution of oxone (234 mg, 0.382 mmols) inwater (3.0 mL). The reaction mixture was stirred at room temperature for20 mins (SM is rapidly converted to a very polar component sulphoxideand then with time to the less polar sulphone product). The reaction wasquenched in water (40 mL) and extracted with EtOAc (3×20 mL). Organicswere washed with brine (30 mL), dried (MgSO₄) and concentrated in vacuoto give a solid. Crude product was purified by column chromatography(SiO₂ : gradient elution; 25%-60% EtOAc:Hexanes) to give sulphone as awhite foamy solid (43 mg, 74%).

¹ H NMR (CDCl₃) δ Unit A: 7.58-7.17 (m, ArH₅), 6.82-6.75 (m, 3-H), 5.87(d, J=16 Hz, 2-H), 4.98-4.86 (m, 5-H), 3.70 (d, J=1.1 Hz, 7-H),2.92-2.89 (m,7-H), 2.61-2.58 (m,4-HH'), 1.94-1.89 (m, 6-H), 1.13 (d,J=7.1 Hz, 6-Me); Unit B: 7.58-7.17 (m, ArH), 7.04 (d, J=7.7 Hz, ArH),6.81 (d, J=8.1 Hz, ArH), 6.54 (d, J=7.5 Hz, NH), 4.98-4.86 (m, 2-H),3.84 (s, 7-OMe), 3.17-2.98 (dq, J_(AB) =14 and 6.6 Hz, 2-HH'); Unit C':7.75 (d, J=7.4 Hz, ArH₂), 7.62 (d, J=6.8 Hz, ArH₂), 7.58-7.17 (m, ArH₄),5.97 (t, J=5.5 Hz, NH), 5.00 (s, SO₂ Me), 4.98-4.86 (m, 2H, 1'-HH'),4.38-4.33 (m, 3'-HH'), 4.25-4.20 (m, 4'-H), 3.40-3.36 (m, 3-HH'), 1.22(s, 2-Me), 1.15 (s, 2-Me); Unit D: 5.19 (q, J_(AB) =5 Hz, 2-H),1.80-1.61 (m, 2H, 3-H, 4-H), 1.57-1.49 (m, 3-H'), 0.91 (s, 5-H₃), 0.89(s, 4-Me) ppm.

Example 13 Cryptophycin 52 ##STR64##

To a stirred solution of sulphone of Example 12 (18 mg, 17.98 umols) indry DMF (2.0 mL) was added neat piperidine (8.9 uL, 90 umols) at roomtemperature and under nitrogen. The resulting solution was stirred for 5h and then concentrated in vacuo to give crude amine as a foam. Theamine was dissolved in toluene (3 mL) and heated at 60° C. undernitrogen for 40 mins. The reaction solution was directly purified bycolumn chromatography (SiO₂ ; gradient elution; 20%-75% EtOAc:Hexanes)to give cryptophycin 52 as a white glass (6.1 mg, 51% over 2 steps).

¹ H NMR (CDCl₃) δ Unit A: 7.45-7.38 (m, ArH₃), 7.31-7.23 (m, ArH₂),6.85-6.76 (m, 3-H), 5.76 (d, J=15.6 Hz, 2-H), 5.27-5.23 (m, 5-H), 2.97(dd, J=7.5 and 1.7 Hz, 7-H), 2.66-2.44 (m, 4-HH'), 1.86-1.67 (m, 6-H),1.19 (d, J=6.9 Hz, 6-Me); Unit B: 7.31-7.23 (m, ArH), 7.09 (dd, J=8.3and 2.0 Hz, ArH), 6.88 (d, J=8.4 Hz, ArH), 5.50 (d J=7.8 Hz, NH), 4.79(q, J=6.4 Hz, 2-H), 3.92 (s, OMe), 3.73 (d, J=1.5 Hz, 8-H), 3.17-3.11(m, 3-HH'); Unit C': 3.47 (dd, J=13.4 and 8.7 Hz, 3-H), 3.17-3.11 (m,3'-H), 1.27 (s, 2-Me), 1.20 (s, 2-Me); Unit D: 4.87 (dd, J=10 and 3.3Hz, 2-H), 1.86-1.67 (m, 2H, 3-H, 4-H), 1.40-1.30 (m, 3-H'), 0.88 (app t,J=6.3 Hz, 6H, 5-H₃, 4-Me) ppm.

Conversion rates and β/α ratios are presented in Table 1 below.Epoxidations were completed in CH₃ CN/aq. H₂ O at 0° C. and pH 7.8-8.2using 4 equivalents of (7) (2 of the 4 equivalents added over 4 hours)and a mixture of Oxone (10 equivalents) and NaHCO₃ (31 equivalents)which was added over 4 hours. For entry 2, all of the ketone (7) wasadded at the beginning.

                                      TABLE 1                                     __________________________________________________________________________    Asymmetric Epoxidation of Cryptophycin Intermediates                          No. Substrate                     Product         β/α ratio                                                                Conversion            __________________________________________________________________________                                                              #STR65##                                                                      #STR66##               - 1 R.sub.1 = 3-Cl-4-methyoxyphenyl Example 1   5:1 >95%                      -                                                                                                                                    #STR67##                                                                      #STR68##               - 2 R.sub.1 = 3-Cl-4-methyoxyphenyl Example 2 9.5:1   85%                     -                                                                                                                                    #STR69##                                                                      #STR70##               - 3 R.sub.1 = 3-Cl-4-methyoxyphenyl Example 5 5-7:1 <10%                   __________________________________________________________________________

We claim:
 1. A process for preparing a compound of the formula ##STR71##wherein G is C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl, C₂ -C₁₂ alkynyl, or Ar;Aris an aromatic or heteroaromatic group or a substituted aromatic orheteroaromatic group; R³ is C₁ -C₆ alkyl; R⁴ and R⁵ are each hydrogen;or R⁴ and R⁵ taken together form a second bond between C-13 and C-14; R⁷and R⁸ are each independently hydrogen or C₁ -C₆ alkyl; or R⁷ and R⁸taken together form a cyclopropyl or cyclobutyl ring; R⁹ is hydrogen, C₁-C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, --(CH₂)_(m) --(C₃-C₅)cycloalkyl or benzyl, wherein m is the integer one to three; R¹⁰ ishydrogen or C₁ -C₆ alkyl; R¹¹ is hydrogen, C₁ -C₆ alkyl, phenyl orbenzyl; R¹⁴ is hydrogen or C₁ -C₆ alkyl; R⁵⁰ is hydrogen or (═O); Y isCH, O, NH, SO, SO₂ or (C₁ -C₃)alkylamino; R⁶ is C₁ -C₆ alkyl,substituted (C₁ -C₆)alkyl, (C₃ -C₈)cycloalkyl, substituted (C₃-C₈)cycloalkyl, a heteroaromatic or substituted heteroaromatic group ora group of formula (IA), (IB) or (IC): ##STR72## R^(6a), R^(6b), andR^(6c) independently are H, halo or OR¹⁸ ; R¹⁵, R¹⁶, and R¹⁷independently are hydrogen, halo, (C₁ -C₆) alkyl, OR¹⁸, O-aryl, NH₂,NR¹⁸ R¹⁹, NO₂, OPO₄ H₂, (C₁ -C₆ alkoxy)phenyl, S-benzyl, CONH₂, CO₂ H,PO₃ H₂, SO₂ R²³, or Z'; R¹⁸ and R¹⁹ independently are hydrogen or C₁ -C₆alkyl; R²³ is hydrogen or (C₁ -C₃)alkyl; Z is --(CH₂)₁₁ -- or (C₃-C₅)cycloalkyl; n is 0, 1, or 2; and Z' is an aromatic or substitutedaromatic group; or a pharmaceutically acceptable salt thereof;comprisingepoxidizing a compound of the formula ##STR73## wherein G, R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴ and R⁵⁰ are as defined above and Y is Y'or S; with an oxidant and a chiral ketone to form a compound of formula(I); and optionally forming a pharmaceutically acceptable salt thereof.2. A process according to claim 1 wherein G is phenyl,para-fluorophenyl, or phenyl substituted with --CH₂ OC(O)(CH₂)_(m') NH₂; R³ is methyl; R⁴ and R⁵ taken together form a second bond between C-13and C-14; R⁹ is C₁ -C₆ alkyl; R¹⁰ is hydrogen; R¹¹ is hydrogen; R¹⁴ ishydrogen; R⁵⁰ is (═O); Y is O; R⁶ is a group of the formula (IA).
 3. Aprocess according to claim 1 wherein said oxidant is Oxone and saidchiral ketone is a compound of the formula ##STR74##
 4. A processaccording to claim 2 wherein G is phenyl.
 5. A process according toclaim 1 wherein said compound of formula (I) is Cryptophycin
 52. 6. Aprocess for preparing a compound of the formula whereinG is C₁ -C₁₂alkyl, C₂ -C₁₂ alkenyl, C₂ -C₁₂ alkynyl, or Ar; Ar is an aromatic orheteroaromatic group or a substituted aromatic or heteroaromatic group;R³ is C₁ -C₆ alkyl; R⁴ and R⁵ are each hydrogen; or R⁴ and R⁵ takentogether form a second bond between C-13 and C-14; R⁸³ is hydrogen, C₁-C₆ alkyl, trichloroethyl, or --CH₂ SR⁸¹ ; R^(30') is hydrogen, analcohol protecting group, or a group of the formula ##STR75## R⁷ and R⁸are each independently hydrogen or C₁ -C₆ alkyl; or R⁷ and R⁸ takentogether form a cyclopropyl or cyclobutyl ring; R⁹ is hydrogen, C₁ -C₆alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, --(CH₂)_(m) --(C₃ -C₅)cycloalkylor benzyl, wherein m is the integer one to three; R¹⁰ is hydrogen or C₁-C₆ alkyl; R¹¹ is hydrogen, C₁ -C₆ alkyl, phenyl or benzyl; R¹⁴ ishydrogen or C₁ -C₆ alkyl; R⁵⁰ is hydrogen or (═O); Y is CH, O, NR¹², S,SO, SO₂, wherein R¹² is H or C₁ -C₃ alkyl; R⁶ is C₁ -C₆ alkyl,substituted (C₁ -C₆)alkyl, (C₃ -C₈)cycloalkyl, substituted (C₃-C₈)cycloalkyl, a heteroaromatic or substituted heteroaromatic group ora group of formula (IA), (IB) or (IC): ##STR76## R^(6a), R^(6b), andR^(6c) independently are H, (C₁ -C₆)alkyl, halo NR¹⁸ R¹⁹ or OR¹⁸ ; R¹⁵,R¹⁶, and R¹⁷ independently are hydrogen, halo, (C₁ -C₆)alkyl, OR¹⁸,O-aryl, NH₂, NR¹⁸ R¹⁹, NO₂, OPO₄ H₂, (C₁ -C₆ alkoxy)phenyl, S-benzyl,CONH₂, CO₂ H, PO₃ H₂, SO₂ R²³, or Z'; R¹⁸ and R¹⁹ independently arehydrogen or C₁ -C₆ alkyl; R²³ is hydrogen or (C₁ -C₃)alkyl; Z is--(CH₂)_(n) -- or (C₃ -C₅)cycloalkyl; n is 0, 1, or 2; and Z' is anaromatic or substituted aromatic group; R⁸¹ is C₁ -C₆ alkyl, C₃ -C₈cycloalkyl, phenyl or benzyl; and R⁸² is a base labile protecting group;or a pharmaceutically acceptable salt thereof; with the proviso thatwhen R⁸³ is --CH₂ SR⁸¹, R³⁰ is not hydrogen or an alcohol protectinggroup;comprising epoxidizing a compound of the formula ##STR77## whereinG, R³, R⁴, R⁵, R⁶, R¹⁴, R^(30') and R⁸³ are as defined above; with anoxidant and a chiral ketone to form a compound of formula (II); andoptionally forming a pharmaceutically acceptable salt thereof.
 7. Aprocess according to claim 6 wherein G is phenyl, para-fluorophenyl, orphenyl substituted with --CH₂ OC(O)(CH₂)_(m') NH₂ ; R³ is methyl; R⁴ andR⁵ taken together form a second bond between C-13 and C-14; R⁹ is C₁ -C₆alkyl; R¹⁰ is hydrogen; R¹¹ is hydrogen; R¹⁴ is hydrogen; R⁵⁰ is (═O); Yis O; R⁶ is a group of the formula (IA), R^(30') is hydrogen.
 8. Aprocess according to claim 6 wherein said oxidant is Oxone and saidchiral ketone is a compound of the formula ##STR78##
 9. A processaccording to claim 7 wherein G is phenyl and R⁸³ is trichloroethyl. 10.A process according to claim 6 wherein said compound of formula (II) isrepresented by the formula
 11. A process according to claim 6 furthercomprising forming a compound of formula (I).
 12. A process forpreparing a compound of formula (I) according to claim 6, furthercomprising the steps of: (a) contacting the compound of formula (II),wherein R^(30') is hydrogen and R⁸³ is a cation, with a thioesterforming agent to form a compound of the formula ##STR79## wherein G, R³,R⁴, R⁵, R⁶ and R¹⁴ are as defined above and R⁸¹ is C₁ -C₆ alkyl, C₃ -C₈cycloalkyl, phenyl or benzyl;(b) coupling a compound of formula (IIc)with a compound of the formula ##STR80## wherein R⁷, R⁸, R⁹, R¹⁰, R¹¹and R⁵⁰ are as defined above and R⁸² is a base labile protecting group,to form a compound of the formula ##STR81## wherein G, R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴, R⁵⁰ R⁸¹, R⁸² and Y are as defined above; (c)oxidizing a compound of formula (8) with an oxidizing agent to form acompound of the formula ##STR82## wherein G, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹⁴, R⁵⁰, R⁸¹ and R⁸² and Y are as defined above and q is aninteger 1 or 2; (d) deprotecting a compound of formula (9) with asuitable deprotecting agent to form a compound of the formula ##STR83##wherein G, R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴, R⁵⁰, Y, q and R⁸¹ areas defined above; and optionally contacting a compound of formula (10)with a cyclizing agent to form a compound of formula (I); and (e)optionally forming a pharmaceutically acceptable salt of a compound offormula (I).
 13. A process according to claim 12 wherein G is phenyl,para-fluorophenyl, or phenyl substituted with --CH₂ OC(O)(CH₂)_(m') NH₂; R³ is methyl; R⁴ and R⁵ taken together form a second bond between C-13and C-14; R⁹ is C₁ -C₆ alkyl; R¹⁰ is hydrogen; R¹¹ is hydrogen; R¹⁴ ishydrogen; R⁵⁰ is (═O); Y is O; and R⁶ is a group of the formula (IA);said deprotecting agent is piperidine; said oxidizing agent is Oxone;said oxidant is Oxone and said chiral ketone is a compound of formula(7) and the pH of the epoxidation step is maintained in the range offrom about 7.0 to about 11.5.
 14. A process according to claim 12wherein said compound of formula (I) is Cryptophycin
 52. 15. A processfor preparing a compound of formula (I) according to claim 6, furthercomprising the steps of:(a) deprotecting a compound formula (II) whereinR^(30') is an alcohol protecting group, with a suitable alkoxydeprotecting agent and further carboxy-deprotecting the compound offormula (II) when R⁸³ is C₁ -C₆ is alkyl, with a suitable base to form acompound of the formula ##STR84## wherein G, R³, R⁴, R⁵, R⁶ and R¹⁴ areas defined above and M⁺ is a cation; (b) contacting the compound offormula (IIb), with a thioester forming agent to form a compound of theformula ##STR85## wherein G, R³, R⁴, R⁵, R⁶ and R¹⁴ are as defined aboveand R⁸¹ is C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, phenyl or benzyl; (c)coupling a compound of formula (IIc) with a compound of the formula##STR86## wherein R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R⁵⁰ are as defined above andR⁸² is a base labile protecting group, to form a compound of the formula##STR87## wherein G, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴, R⁵⁰ R⁸¹,R⁸² and Y are as defined above; (d) oxidizing a compound of formula (8)with an oxidizing agent to form a compound of the formula ##STR88##wherein G, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴, R⁵⁰, R⁸¹ and R⁸²and Y are as defined above and q is an integer 1 or 2; (e) deprotectinga compound of formula (9) with a suitable deprotecting agent to form acompound of the formula ##STR89## wherein G, R³, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹⁴, R⁵⁰, Y, q and R⁸¹ are as defined above; and optionallycontacting a compound of formula (10) with a cyclizing agent to form acompound of formula (I); and (f) optionally forming a pharmaceuticallyacceptable salt of a compound of formula (I).
 16. A process according toclaim 15 wherein G is phenyl, para-fluorophenyl, or phenyl substitutedwith --CH₂ OC(O)(CH₂)_(m') NH₂ ; R³ is methyl; R⁴ and R⁵ taken togetherform a second bond between C-13 and C-14; R⁹ is C₁ -C₆ alkyl; R¹⁰ ishydrogen; R¹¹ is hydrogen; R¹⁴ is hydrogen; R⁵⁰ is (═O); Y is O; and R⁶is a group of the formula (IA); said deprotecting agent is piperidine;said oxidizing agent is Oxone; said oxidant is Oxone and said chiralketone is a compound of formula (7).
 17. A process according to claim 15wherein said compound of formula (I) is Cryptophycin
 52. 18. A processfor preparing a compound of formula (I) according to claim 6 furthercomprising the steps of:(a) oxidizing a compound of formula (II) whereinR^(30') is a compound of the formula ##STR90## and R⁸³ is --CH₂ SR⁸¹,with an oxidizing agent to form a compound of the formula ##STR91##wherein G, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴, R⁵⁰, R⁸¹ and R⁸²and Y are as defined above and q is an integer 1 or 2; (b) deprotectinga compound of formula (9) with a suitable deprotecting agent to form acompound of the formula ##STR92## wherein G, R³, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹⁴, R⁵⁰, Y, q and R⁸¹ are as defined above; and optionallycontacting a compound of formula (10) with a cyclizing agent to form acompound of formula (I); and (c) optionally forming a pharmaceuticallyacceptable salt of a compound of formula (I).
 19. A process according toclaim 18 wherein G is phenyl, para-fluorophenyl, or phenyl substitutedwith --CH₂ OC(O)(CH₂)_(m') NH₂ ; R³ is methyl; R⁴ and R⁵ taken togetherform a second bond between C-13 and C-14; R⁹ is C₁ -C₆ alkyl; R¹⁰ ishydrogen; R¹¹ is hydrogen; R¹⁴ is hydrogen; R⁵⁰ is (═O); Y is O; and R⁶is a group of the formula (IA); said deprotecting agent is piperidine;said oxidizing agent is Oxone; said oxidant is Oxone and said chiralketone is a compound of formula (7).
 20. A process according to claim 18wherein said compound of formula (I) is Cryptophycin
 52. 21. A processfor preparing a compound of formula (I) according to claim 6, furthercomprising the steps of(a) coupling a compound of formula (II), whereinR^(30') is hydrogen and R⁸³ is trichloroethyl, with a compound of theformula ##STR93## wherein R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R⁵⁰ are as definedabove and R⁸² is a base labile protecting group, to form a compound ofthe formula ##STR94## wherein G, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹⁴, R⁵⁰, R⁸² and Y are as defined above; (b) treating a compound offormula (18) with a suitable base-deprotecting agent to provide acompound of the formula ##STR95## wherein G, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹⁴, R⁵⁰ and Y are as defined above; (c) cyclizing a compoundof formula (19) with a suitable ring-closing agent to provide a compoundof formula (I); and (d) optionally forming a pharmaceutically acceptablesalt of a compound of formula (I).
 22. A process according to claim 21wherein G is phenyl, para-fluorophenyl, or phenyl substituted with --CH₂OC(O)(CH₂)_(m') NH₂ ; R³ is methyl; R⁴ and R⁵ taken together form asecond bond between C-13 and C-14; R⁹ is C₁ -C₆ alkyl; R¹⁰ is hydrogen;R¹¹ is hydrogen; R¹⁴ is hydrogen; R⁵⁰ is (═O); Y is O; and R⁶ is a groupof the formula (IA); said oxidizing agent is Oxone; said oxidant isOxone and said chiral ketone is a compound of formula (7).
 23. A processaccording to claim 21 wherein said compound of formula (I) isCryptophycin
 52. 24. A process for preparing a compound of formula (I)according to claim 6, further comprising the steps of(a) deprotecting acompound of formula (II) wherein R^(30') is a compound of the formula##STR96## and R⁸³ is trichloroethyl, with a suitable base-deprotectingagent to form a compound of the formula ##STR97## wherein G, R³, R⁴, R⁵,R⁶ and R¹⁴ are as defined above; (b) cyclizing a compound of formula(19) with a suitable ring-closing agent to provide a compound of formula(I); and (c) optionally forming a pharmaceutically acceptable salt of acompound of formula (I).
 25. A process according to claim 24 wherein Gis phenyl, para-fluorophenyl, or phenyl substituted with --CH₂OC(O)(CH₂)_(m') NH₂ ; R³ is methyl; R⁴ and R⁵ taken together form asecond bond between C-13 and C-14; R⁹ is C₁ -C₆ alkyl; R¹⁰ is hydrogen;R¹¹ is hydrogen; R¹⁴ is hydrogen; R⁵⁰ is (═O); Y is O; and R⁶ is a groupof the formula (IA); said oxidizing agent is Oxone; said oxidant isOxone and said chiral ketone is a compound of formula (7).
 26. A processaccording to claim 24 wherein said compound of formula (I) isCryptophycin
 52. 27. A compound of the formula ##STR98## wherein G is C₁-C₁₂ alkyl, C₂ -C₁₂ alkenyl, C₂ -C₁₂ alkynyl, or Ar;Ar is an aromatic orheteroaromatic group or a substituted aromatic or heteroaromatic group;R³ is C₁ -C₆ alkyl; R⁴ and R⁵ are each hydrogen; or R⁴ and R⁵ takentogether form a second bond between C-13 and C-14; R¹⁴ is hydrogen or C₁-C₆ alkyl; R⁶ is C₁ -C₆ alkyl, substituted (C₁ -C₆)alkyl, (C₃-C₈)cycloalkyl, substituted (C₃ -C₈)cycloalkyl, a heteroaromatic orsubstituted heteroaromatic group or a group of formula (IA), (IB) or(IC): ##STR99## R^(6a), R^(6b), and R^(6c) independently are H, halo orOR¹⁸ ; R¹⁵, R¹⁶, and R¹⁷ independently are hydrogen, halo, (C₁-C₆)alkyl, OR¹⁸, O-aryl, NH₂, NR¹⁸ R¹⁹, NO₂, OPO₄ H₂, (C₁ -C₆alkoxy)phenyl, S-benzyl, CONH₂, CO₂ H, PO₃ H₂, SO₂ R²³, or Z'; R¹⁸ andR¹⁹ independently are hydrogen or C₁ -C₆ alkyl; R²³ is hydrogen or (C₁-C₃)alkyl; Z is --(CH₂)_(n) -- or (C₃ -C₅)cycloalkyl; n is 0, 1, or 2;and Z' is an aromatic or substituted aromatic group; or apharmaceutically acceptable salt thereof.
 28. A compound according toclaim 27 wherein G is phenyl, para-fluorophenyl, or phenyl substitutedwith --CH₂ OC(O)(CH₂)_(m') NH₂ ; R³ is methyl; R⁴ and R⁵ taken togetherform a second bond between C-13 and C-14; R¹⁴ is hydrogen; and R⁶ is agroup of the formula (IA).
 29. A compound according to claim 27 whereinsaid compound is represented by the formula ##STR100##30.
 30. A compoundof the formula whereinG is C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl, C₂ -C₁₂alkynyl, or Ar; Ar is an aromatic or heteroaromatic group or asubstituted aromatic or heteroaromatic group; R³ is C₁ -C₆ alkyl; R⁴ andR⁵ are each hydrogen; or R⁴ and R⁵ taken together form a second bondbetween C-13 and C-14; R⁷ and R⁸ are each independently hydrogen or C₁-C₆ alkyl; or R⁷ and R⁸ taken together form a cyclopropyl or cyclobutylring; R⁹ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,--(CH₂)_(m) --(C₃ -C₅)cycloalkyl or benzyl, wherein m is the integer oneto three; R¹⁰ is hydrogen or C₁ -C₆ alkyl; R¹¹ is hydrogen, C₁ -C₆alkyl, phenyl or benzyl; R¹⁴ is hydrogen or C₁ -C₆ alkyl; R⁵⁰ ishydrogen or (═O); Y is CH, O, NH, S, SO, SO₂ or (C₁ -C₃)alkylamino; R⁶is C₁ -C₆ alkyl, substituted (C₁ -C₆)alkyl, (C₃ -C₈)cycloalkyl,substituted (C₃ -C₈)cycloalkyl, a heteroaromatic or substitutedheteroaromatic group or a group of formula (IA), (IB) or (IC):##STR101## R^(6a), R^(6b), and R^(6c) independently are H, halo or OR¹⁸; R¹⁵, R¹⁶, and R¹⁷ independently are hydrogen, halo, (C₁ -C₆)alkyl,OR¹⁸, O-aryl, NH₂, NR¹⁹ R¹⁹, NO₂, OPO₄ H₂, (C₁ -C₆ alkoxy)phenyl,S-benzyl, CONH₂, CO₂ H, PO₃ H₂, SO₂ R²³, or Z'; R¹⁸ and R¹⁹independently are hydrogen or C₁ -C₆ alkyl; R²³ is hydrogen or (C₁-C₃)alkyl; Z is --(CH₂)_(n) -- or (C₃ -C₅)cycloalkyl; n is 0, 1, or 2;Z' is an aromatic or substituted aromatic group; and R⁸² is a baselabile protecting group; or a pharmaceutically acceptable salt thereof.31. A compound according to claim 30 wherein G is phenyl,para-fluorophenyl, or phenyl substituted with --CH₂ OC(O)(CH₂)_(m') NH₂; R³ is methyl; R⁴ and R⁵ taken together form a second bond between C-13and C-14; R⁹ is C₁ -C₆ alkyl; R¹⁰ is hydrogen; R¹¹ is hydrogen; R¹⁴ ishydrogen; R⁵⁰ is (═O); Y is O; and R⁶ is a group of the formula (IA).32. A compound according to claim 30 wherein said compound isrepresented by the formula ##STR102##
 33. A compound of the formulawhereinG is C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl, C₂ -C₁₂ alkynyl, or Ar; Aris an aromatic or heteroaromatic group or a substituted aromatic orheteroaromatic group; R³ is C₁ -C₆ alkyl; R⁴ and R⁵ are each hydrogen;or R⁴ and R⁵ taken together form a second bond between C-13 and C-14; R⁷and R⁸ are each independently hydrogen or C₁ -C₆ alkyl; or R⁷ and R⁸taken together form a cyclopropyl or cyclobutyl ring; R⁹ is hydrogen, C₁-C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, --(CH₂)_(m) --(C₃-C₅)cycloalkyl or benzyl, wherein m is the integer one to three; R¹⁰ ishydrogen or C₁ -C₆ alkyl; R¹¹ is hydrogen, C₁ -C₆ alkyl, phenyl orbenzyl; R¹⁴ is hydrogen or C₁ -C₆ alkyl; R⁵⁰ is hydrogen or (═O); Y isCH, O, NH, S, SO, SO₂ or (C₁ -C₃)alkylamino; R⁶ is C₁ -C₆ alkyl,substituted (C₁ -C₆)alkyl, (C₃ -C₈)cycloalkyl, substituted (C₃-C₈)cycloalkyl, a heteroaromatic or substituted heteroaromatic group ora group of formula (IA), (IB) or (IC): ##STR103## R^(6a), R^(6b), andR^(6c) independently are H, halo or OR¹⁸ ; R¹⁵, R¹⁶, and R¹⁷independently are hydrogen, halo, (C₁ -C₆)alkyl, OR¹⁸, O-aryl, NH₂, NR¹⁸R¹⁹, NO₂, OPO₄ H₂, (C₁ -C₆ alkoxy)phenyl, S-benzyl, CONH₂, CO₂ H, PO₃H₂, SO₂ R²³, or Z'; R¹⁸ and R¹⁹ independently are hydrogen or C₁ -C₆alkyl; R²³ is hydrogen or (C₁ -C₃)alkyl; Z is --(CH₂)_(n) -- or (C₃-C₅)cycloalkyl; n is 0, 1, or 2; and Z' is an aromatic or substitutedaromatic group; or a pharmaceutically acceptable salt thereof.
 34. Acompound according to claim 33 wherein G is phenyl, para-fluorophenyl,or phenyl substituted with --CH₂ OC(O)(CH₂)_(m') NH₂ ; R³ is methyl; R⁴and R⁵ taken together form a second bond between C-13 and C-14; R⁹ is C₁-C₆ alkyl; R¹⁰ is hydrogen; R¹¹ is hydrogen; R¹⁴ is hydrogen; R⁵⁰ is(═O); Y is O; and R⁶ is a group of the formula (IA).
 35. A compoundaccording to claim 33 wherein said compound is represented by theformula ##STR104##
 36. A process for preparing a compound of the formulawhereinG is C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl, C₂ -C₁₂ alkynyl, or Ar; Aris an aromatic or heteroaromatic group or a substituted aromatic orheteroaromatic group; R³ is C₁ -C₆ alkyl; R⁴ and R⁵ are each hydrogen;or R⁴ and R⁵ taken together form a second bond between C-13 and C-14; R⁷and R⁸ are each independently hydrogen or C₁ -C₆ alkyl; or R⁷ and R⁸taken together form a cyclopropyl or cyclobutyl ring; R⁹ is hydrogen, C₁-C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, --(CH₂)_(m) --(C₃-C₅)cycloalkyl or benzyl, wherein m is the integer one to three; R¹⁰ ishydrogen or C₁ -C₆ alkyl; R¹¹ is hydrogen, C₁ -C₆ alkyl, phenyl orbenzyl; R¹⁴ is hydrogen or C₁ -C₆ alkyl; R⁵⁰ is hydrogen or (═O); Y isCH, O, NR¹², S, SO, SO₂, wherein R¹² is H or C₁ -C₃ alkyl; R⁶ is C₁ -C₆alkyl, substituted (C₁ -C₆)alkyl, (C₃ -C₈)cycloalkyl, substituted (C₃-C₈)cycloalkyl, a heteroaromatic or substituted heteroaromatic group ora group of formula (IA), (IB) or (IC): ##STR105## R^(6a), R^(6b), andR^(6c) independently are H, (C₁ -C₆)alkyl, halo NR¹⁸ R¹⁹ or OR¹⁸ ; R¹⁵,R¹⁶, and R¹⁷ independently are hydrogen, halo, (C₁ -C₆)alkyl, OR¹⁸,O-aryl, NH₂, NR¹⁸ R¹⁹, NO₂, OPO₄ H₂, (C₁ -C₆ alkoxy)phenyl, S-benzyl,CONH₂, CO₂ H, PO₃ H₂, SO₂ R²³, or Z'; R¹⁸ and R¹⁹ independently arehydrogen or C₁ -C₆ alkyl; R²³ is hydrogen or (C₁ -C₃)alkyl; R⁸¹ is C₁-C₆ alkyl, C₃ -C₈ cycloalkyl, phenyl or benzyl; R⁸² is a base labileprotecting group; Z is --(CH₂)_(n) -- or (C₃ -C₅)cycloalkyl; n is 0, 1,or 2; q is an integer 1 or 2; and Z' is an aromatic or substitutedaromatic group; or a pharmaceutically acceptable salt thereof;comprisingoxidizing a compound of the formula ##STR106## wherein G, R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴, R⁵⁰, R⁸¹, R⁸² and Y are as defined above,with an oxidizing agent to form a compound of formula (9) and optionallyforming a pharmaceutically acceptable salt of a compound of formula (9).37. A process according to claim 36 wherein G is phenyl,para-fluorophenyl, or phenyl substituted with --CH₂ OC(O)(CH₂)_(m') NH₂; R³ is methyl; R⁴ and R⁵ taken together form a second bond between C-13and C-14; R⁹ is C₁ -C₆ alkyl; R¹⁰ is hydrogen; R¹¹ is hydrogen; R¹⁴ ishydrogen; R⁵⁰ is (═O); Y is O; and R⁶ is a group of the formula (IA) andthe oxidizing agent is Oxone.
 38. A process for preparing a compound offormula (I) according to claim 36, further comprising the steps of:(a)deprotecting a compound of formula (9) with a suitable deprotectingagent to form a compound of the formula ##STR107## wherein G, R³, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴, R⁵⁰, Y, q and R⁸¹ are as defined above;and optionally contacting a compound of formula (10) with a cyclizingagent to form a compound of formula (I); and (b) optionally forming apharmaceutically acceptable salt of a compound of formula (I).
 39. Aprocess according to claim 38 wherein G is phenyl, para-fluorophenyl, orphenyl substituted with --CH₂ OC(O)(CH₂)_(m') NH₂ ; R³ is methyl; R⁴ andR⁵ taken together form a second bond between C-13 and C-14; R⁹ is C₁ -C₆alkyl; R¹⁰ is hydrogen; R¹¹ is hydrogen; R¹⁴ is hydrogen; R⁵⁰ is (═O); Yis O; and R⁶ is a group of the formula (IA); said deprotecting agent ispiperidine; said oxidizing agent is Oxone; said oxidant is Oxone andsaid chiral ketone is a compound of formula (7).
 40. A process accordingto claim 38 wherein said compound of formula (I) is Cryptophycin 52.